Scale-up of the green synthesis of azacycloalkanes and isoindolines under microwave irradiation

Article abstract of DOI:10.1021/op0601722

A green approach to N-heterocyclization reactions ranging in scale from 20 mmol to 1 mol performed under microwave irradiation in open vessels has been investigated. By using water as the solvent and no transition metal catalysts, N-heterocycles are formed in a fraction of the time needed for conventional synthesis of these compounds. The obtained yields indicate that reactions can be performed at atmospheric pressure using the same reaction conditions as the corresponding sealed-vessel reactions. Single-mode and multimode microwave cavities have been used for open-vessel synthesis without changing reaction times producing similar yields.

Full text of DOI:10.1021/op0601722

Organic Process Research & Development 2006, 10, 1233−1237
Scale-Up of the Green Synthesis of Azacycloalkanes and Isoindolines
under Microwave Irradiation
T. Michael Barnard,* Grace S. Vanier, and Michael J. Collins, Jr.
Synthesis DiVision, CEM Corporation, 3100 Smith Farm Road, Matthews, North Carolina 28106, U.S.A.
7
Abstract:
Demko and Sharpless found that 1 H-tetrazoles can be
A green approach to N-heterocyclization reactions ranging in
scale from 20 mmol to 1 mol performed under microwave
irradiation in open vessels has been investigated. By using water
as the solvent and no transition metal catalysts, N-heterocycles
are formed in a fraction of the time needed for conventional
synthesis of these compounds. The obtained yields indicate that
reactions can be performed at atmospheric pressure using the
same reaction conditions as the corresponding sealed-vessel
reactions. Single-mode and multimode microwave cavities have
been used for open-vessel synthesis without changing reaction
times producing similar yields.
synthesized in water despite the relative insolubility of the
starting materials. Sharpless later found that water increases
8
the rate of reactivity for a variety of “on water” chemistries
and is continuing to research this phenomenon. The use of
water as a reaction solvent also allows for the easy separation
of the product from the solvent due to the limited solubility
of organic compounds in water at room temperature.
Over the past two decades, the use of microwaves for
chemical syntheses has drastically increased as can be
implied by the increasing number of publications in the field
9
,10
of microwave chemistry.
Microwave-assisted organic
synthesis has been shown to enhance the rate of reactions
and improve product yields, as well as be energy efficient.11
A growing area of interest in microwave-promoted synthesis
Introduction
1
2
is the scaling-up of reactions. This can be achieved in two
Chemicals used in the production of goods have, over
the years, damaged the environment through pollution and
waste. Increased environmental awareness along with the
1
3
14-16
possible ways: continuous flow or a batch process.
Continuous flow microwave reactors can be problematic
when processing solids, heterogeneous reaction mixtures, and
1
high costs associated with environmental pollution control
1
0,16
high viscosity liquids.
parallel batch reactors,
Batch processes can involve
where multiple reaction vessels
are challenging chemists to find alternative ways to harness
the benefits chemistry has to offer. Some of these alternatives
include the use of more environmentally friendly solvents,
9
d,16
are placed in the microwave at one time, or use one large
1
4-16
2
vessel.
microwave reactors, and alternative reaction conditions.
Microwave synthesis can be performed either under
sealed-vessel or open-vessel conditions. Reactions performed
in sealed vessels can reach temperatures much higher than
the boiling point of the solvent used at elevated pressure. In
open-vessel microwave assisted reactions, reactions are
carried out at atmospheric pressure; yet solvents can still
In the search for green chemistries, aqueous media is one
of the greenist for reactions next to neat. Water as a solvent
has the advantage of being readily available, inexpensive,
3
and nontoxic, though it is rarely looked at due to the need
4
for additives such as phase transfer catalysts due to the
limited aqueous solubility of organic compounds. However,
as water increases in temperature, it becomes more nonpolar,
more acidic, and less dense, and its dielectric constant
decreases, allowing organic compounds to become more
(
6) Hayes, B. L. MicrowaVe Synthesis: Chemsitry at the Speed of Light; CEM
Publishing: Matthews, NC, 2002.
(
(
7) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945.
8) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
5
,6
soluble eliminating the need for phase transfer catalysts.
(
9) For a review on microwave chemistry, see: (a) Nuchter, M.; Ondruschka,
B.; Gum, A. Green Chem. 2004, 6, 128. (b) Loupy, A., Ed. MicrowaVes in
Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
2002. (c) Tierney, J. P.; Lidstrom, P., Eds. MicrowaVe Assisted Organic
Synthesis; Blackwell Publishing Ltd: Oxford, 2005. (d) Kappe, C. O.;
Stadler, A. MicrowaVes in Organic and Medicinal Chemistry; WILEY-
VCH: Weinheim, 2005.
*
To whom correspondence should be addressed. E-mail: mike.barnard@
cem.com.
(1) Pereira, C. J. Chem. Eng. Sci. 1999, 54, 1959.
(
2) Varma, R. S. AdVances in Green Chemistry: Chemical Syntheses Using
MicrowaVe Irradiation; AstraZeneca Research Foundation, Kavitha Print-
ers: Bangalore, India, 2002.
(
3) For a review on reactions in aqueous media, see: (a) Sinou, D. In Modern
SolVents in Organic Synthesis; Knochel, P., Ed.; Springer-Verlag: Berlin
Heidelberg, 1999; pp 41-60. (b) Lubineau, A.; Auge, J. In Modern SolVents
in Organic Synthesis; Knochel, P., Ed.; Springer-Verlag: Heidelberg, 1999;
pp 1-40. (c) Li, C.-J.; Chen, L. Organic Reactions in Aqueous Media;
Wiley: New York, 1997. (d) Li, C.-J.; Chen, L. Chem. Soc. ReV. 2006,
(10) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
9225.
(11) Gronnow, M. J.; White, R. J.; Clark, J.; Macquarrie, D. Org. Process Res.
DeV. 2005, 9, 516.
(12) Tilstam, U. Org. Process Res. DeV. 2004, 8, 421.
(13) (a) Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem. 1994, 59,
3408. (b) Bagley, M. C.; Jenkins, R. L.; Lubinu, M. C.; Mason, C.; Wood,
R. J. Org. Chem. 2005, 70, 7003.
(14) Leadbeater, N. E.; Williams, V. A.; Barnard, T. M.; Collins, M. J. Org.
Process Res. DeV. 2006, 10, 833.
3
5, 68. (e) Cornils, B.; Herrmann, W. A., Eds. Aqueous-Phase Organo-
metallic Catalysis: Concepts and Applications, 2nd ed.; Wiley-VCH:
Weinheim, 2004. (f) Lindstrom, U. M. Chem. ReV. 2002, 102, 2751. (g)
Grieco, P. A., Ed. Organic Synthesis in Water; Blackie Academic and
Professional: London, 1998.
(15) Arvela, R. K.; Leadbeater, N. E.; Collins, M. J. Tetrahedron 2005, 61,
9349.
(16) Loones, K. T. J.; Maes, B. U. W.; Rombouts, G.; Hostyn, S.; Diels, G.
Tetrahedron 2005, 61, 10338.
(
4) Zhang, T. Y. In Handbook of Green Chemistry & Technology; Clark, J.,
Macquarrie, D., Eds.; Blackwell Science Ltd.: Oxford, 2002; p 306.
5) Strauss, C. R. Aust. J. Chem. 1999, 52, 83.
(
1
0.1021/op0601722 CCC: $33.50 © 2006 American Chemical Society
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Published on Web 10/21/2006

Scheme 1N-Heterocyclizations performed by Varma and
Ju
microwave cavity using sealed vessels at moderate temper-
atures. The reactions were heated to and maintained at a
temperature of 120 °C with pressures of 50 psi for 20 min.
Our first step in scaling-up the reactions was transitioning
from sealed-vessel to open-vessel reactions. Previous work
has shown open-vessel reactions give yields equal to, if not
greater than, those performed in sealed vessels with reaction
temperatures still going above the solvent boiling point.9
We performed open-vessel reactions on a 20 mmol scale, in
a single-mode microwave cavity, using a standard 100 mL
round-bottom flask fitted with a reflux condenser. These
open-vessel reactions were heated to reflux, where the
temperature limit was set to 120 °C allowing for maximum
power input, and allowed to reflux for 20 min. Actual
temperatures reached varied between 103 °C and 115 °C,
thus demonstrating that water can reach temperatures above
the boiling point while remaining at atmospheric pressure.
Comparisons for the different reactions performed in
sealed and open vessels can be found in Table 1. We have
confirmed that the yields for open-vessel synthesis in a
single-mode microwave cavity are equal to, and in some
cases much greater than, those obtained in sealed vessels.
Reactions producing higher yields (entries 2 and 3) could
possibly be attributed to the release of the volatile gas HBr,
shifting the reaction equilibrium to the product side.
23,24
d,10,18,27
reach temperatures that are 10-20 °C above their boiling
6
,10,17,18
points,
which may be explained by the occurrence of
instantaneous hot spots.1
7,19
Open-vessel synthesis allows for
any gases that may be generated in a reaction to evolve from
the reaction environment possibly causing reactions to
progress further to completion than when performed in a
sealed vessel. Also, open-vessel reactions can be performed
using standard laboratory glassware, such as round-bottom
flasks and reflux condensers, in the microwave cavity
allowing reactions to be carried out on a larger scale.
There are two types of microwave cavities, single-mode
and multimode. Single-mode cavities are much smaller than
multimode cavities and have only one mode present. The
microwave energy in a single-mode cavity is directed into
the reaction vessel, whereas in a multimode cavity the
microwave energy not being absorbed by the reaction
solution is being reflected by the walls of the cavity. A more
To scale-up further, we moved to a multimode system
where we are able to use round-bottom flasks up to 5 L.
Previous research has shown that transitioning from single-
mode to multimode microwave systems has produced similar
yields with no significant change in reaction times.1 Our
research confirmed these results (Tables 2 and 3). Open-
vessel reactions carried out in the multimode cavity were
heated and allowed to reflux for 20 min. The temperature
limit was set at 110 °C, and actual temperatures reached
varied between 100 °C and 106 °C.
6,27
detailed explanation of single-mode and multimode cavities
can be found elsewhere.20
Results and Discussion
Nitrogen containing heterocycles are present in many
natural products and show great biological activity in
pharmaceuticals.21 Conventional syntheses of these com-
Reactions performed on the 0.2, 0.6, and 1.0 mol scales
were irradiated with 300, 600, and 1200 W, respectively.
Each reaction was rapidly heated by selecting a power input
to allow reactions to reach reflux in approximately 10 min
making the overall reaction time from heating to reaction
completion 30 min. A considerable time savings can be seen
for microwave synthesis compared to conventional synthesis
when comparing the 30 min needed for reactions in a
microwave to the time needed for conventional synthesis
where 30 min are needed to heat the reaction solution to
temperature and then maintaining this temperature for an
additional 5 h in order to reach reaction completion.28
Isolation of the synthesized compounds consisted of
simple washing steps. No time-consuming column chroma-
tography was needed, eliminating the need for large quanti-
ties of solvent use. Liquid products (1 and 3) were extracted
into a minimal amount of ethyl acetate and washed with
deionized water and then the solvent was removed in vacuo,
whereas the solid products were filtered and washed with
deionized water followed by chilled hexanes. These isolation
pounds require long reaction times, expensive catalysts, and
hazardous solvents.2
2-25
Microwave assisted syntheses of
N-heterocycles has led to a decrease in reaction time,
improved yields, and the use of more benign solvents and
2
3,24,26
has eliminated the need for transition metal catalysts.
This research uses water as the solvent and no metal catalyst
for the synthesis of N-azacycloalkanes and N-isoindolines.
Reaction times are minimal with greatly improved yields
compared to those of conventional syntheses of these
2
4
compounds.
This research is based on the work of Varma and Ju23,24
Scheme 1) where reactions were performed in a single-mode
(
(
17) See ref 9b, pp 115-146.
(18) (a) Baghurst, D. R.; Mingos, D. M. J. Chem. Soc., Chem. Commun. 1992,
6
74. (b) Mingos, D. M.; Baghurst, D. R. Chem. Soc. ReV. 1991, 20, 1.
(
(
(
(
19) See ref 9b, p 345.
20) See ref 9b, pp 1-34.
21) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
22) (a) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677. (b)
Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066.
23) Ju, Y.; Varma, R. S. J. Org. Chem. 2006, 71, 134.
24) Ju, Y.; Varma, R. S. Org. Lett. 2005, 7, 2409.
25) (a) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417. (b) Zim, D.;
Buchwald, S. L. Org. Lett. 2003, 5, 2413.
(
(
(
(27) Stadler, A.; Pichler, S.; Horeis, G.; Kappe, C. O. Tetrahedron 2002, 58,
3177.
(28) Tsuji, Y.; Huh, K.-T.; Ohsugi, Y.; Watanabe, Y. J. Org. Chem. 1985, 50,
(26) Xu, G.; Wang, Y.-G. Org. Lett. 2004, 6, 985.
1365.
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Vol. 10, No. 6, 2006 / Organic Process Research & Development

Table 1. N-Heterocyclization reactions in water performed in a monomode microwave apparatus using sealed and open vessels
a
2 3 2 2 3 2
mmol of amine, 1.1 mmol of dihalide, 1.1 mmol of K CO , 2 mL of H CO , 40 mL of H O.
O. b 20 mmol of amine, 22 mmol of dihalide, 22 mmol of K
1
Table 2. Scale-up of open-vessel microwave promoted azacycloalkane synthesis in water
a
Reactions carried out in a single-mode microwave cavity. b Reactions carried out in a multimode microwave cavity.
procedures held true for all compounds synthesized from the
mmol scale (5 affording 0.305 g) to the 1 mol scale (5
simplicity of switching between single-mode and multimode
microwave cavities.
1
affording 267 g). The ease of isolation comes from the fact
that no byproducts were detected after the reactions. The
only impurities found in the products were unreacted starting
material that could be easily washed away in the case of the
isoindolines.
The green synthesis and purification of N-heterocycles is
shown using water as the solvent with no transition metal
catalysts and eliminating the need for large quantities of
solvent for purification. Reactions are completed in 30 min
with minimal time needed for purification affording hundreds
of grams of product.
Conclusion
Experimental Section
N-Heterocyclization reactions performed under microwave
irradiation can easily be scaled 1000-fold from mmole to
mole quantities in approximately 30 min with no decrease
in yield. We have shown the ease in translating reaction
conditions from sealed vessels to open vessels and the
General. All reagents were obtained from commercial
suppliers and were used without further purification. GC-
MS analysis was run using a Perkin-Elmer AutoSystemXL
Gas Chromatograph/TurboMass mass spectrometer equipped
Vol. 10, No. 6, 2006 / Organic Process Research & Development
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Table 3. Scale-up of open-vessel microwave promoted isoindoline synthesis in water
a
Reactions carried out in a single-mode microwave cavity. b Reactions carried out in a multimode microwave cavity.
with a column Elite-5MS (30 m × 0.25 mm × 0.25 µm).
All samples were examined under the following temperature
gradient: Temp 1, 50 °C (1 min); Temp 2, 210 °C (5.17
min); rate 32.0 °C/min; Temp 3, 300 °C (5.50 min); rate
Upon cooling, the reaction mixture is extracted with ethyl
acetate, the organic layer was washed with distilled water,
and the solvent was removed in vacuo giving 2.94 g (87%
1
isolated yield, 94% purity) of N-phenylpiperidine. H and
1
13
13
2
2
7.0 °C/min. H and C NMR spectra were recorded at
C NMR data are consistent with those found in the
1
22,26,28,29
93 K on a BRUKER AVANCE-400 spectrometer ( H 400
literature.
1
3
MHz, C 100 MHz).
Representative Example of the Synthesis of Isoindo-
lines on a 20 mmol Scale: Single-Mode Microwave
Cavity. To a 100 mL round-bottom flask was added aniline
(1.9 g, 20 mmol), 1,2-bis(chloromethyl)benzene (3.9 g, 22
mmol), and potassium carbonate (3.2 g, 23 mmole) in 40
mL of distilled water. The reaction vessel was placed in a
single-mode focused microwave reactor and fitted with a
reflux condenser. The reaction was irradiated with 150 W
to a temperature of 105 °C (reflux) where it was held for 20
min. Upon cooling, the solid product is filtered, washed with
distilled water followed by chilled hexanes, and dried in
vacuo giving 3.86 g (99% isolated yield, 99% purity)
Description of the Microwave Apparatus. Reactions in
sealed vessels on the 1 mmol scale along with the open-
vessel reactions on the 20 mmol scale were performed in a
commercially available single-mode microwave system
(CEM Discover), with a power output ranging from 0 to
300 W. Reactions were performed in a 100 mL round-bottom
flask fitted with a reflux condenser. The temperature was
monitored via an IR sensor located directly below the vessel.
The vessel contents were stirred by means of an adjustable
speed electromagnet located below the microwave cavity and
a Teflon-coated magnetic stir bar inside the vessel. Tem-
perature and power profiles were recorded using computer
controlled software. Subsequent reactions were scaled up to
1
13
N-phenylisoindoline. H and C NMR data are consistent
3
0
with those found in the literature.
1
mole and performed in a multimode microwave apparatus
Representative Example of the Scale-Up of Azacyclo-
alkanes on a 0.2 mol Scale: Multimode Microwave
(CEM MARS, Microwave Accelerated Reaction System),
3
1
with the power output ranging from 0 to 1200 W. Reactions
were performed on a 0.2 mol, 0.6 mol, and 1.0 mol scale in
a 1, 3, and 5 L round-bottom flask, respectively. The
temperature was monitored via a fiber optic probe inserted
directly in the reaction mixture. Stirring was achieved by
means of a rotating magnetic plate located below the floor
of the microwave cavity and a Teflon-coated magnetic stir
bar in the reaction vessel.
Cavity. To a 1 L round-bottom flask was added aniline
(18.9 g, 0.2 mol), 1,5-dibromopentane (56.0 g, 0.22 mol),
and potassium carbonate (32.5 g, 0.23 mol) in 400 mL of
distilled water. The reaction vessel was placed in a multi-
mode microwave reactor and fitted with a reflux condenser.
The reaction was irradiated with 300 W of power to a
temperature of 110 °C (reflux) where it was held for 20 min.
Upon cooling, the reaction mixture is extracted with ethyl
acetate, the organic layer was washed with distilled water,
and the solvent was removed in vacuo giving 26.8 g (83%
Representative Example of the Synthesis of Azacyclo-
alkanes on a 20 mmol Scale: Single-Mode Microwave
Cavity. To a 100 mL round-bottom flask was added aniline
(
1.9 g, 20 mmole), 1,5-dibromopentane (5.6 g, 22 mmole),
(29) Sassaman, M. B. Tetrahedron 1996, 52, 10835.
(
30) (a) Kreher, R. P.; Seubert, J.; Schmitt, D.; Use, G.; Kohl, N. Chem.-Ztg.
988, 112, 85. (b) Nishio, T.; Okuda, N. J. Org. Chem. 1992, 57, 4000.
and potassium carbonate (3.2 g, 23 mmole) in 40 mL of
distilled water. The reaction vessel was placed in a single-
mode focused microwave reactor and fitted with a reflux
condenser. The reaction was irradiated with 150 W to a
temperature of 115 °C (reflux) where it was held for 20 min.
1
1
(
c) N-Bromophenylisoindoline: H NMR (400 MHz) (CDCl
3
) 4.62 (s, 4H),
6.56 (d, j ) 8.6 Hz, 2H), 7.31-7.46 (m, 6H); C NMR (100 MHz) (CDCl
3.8, 108.2, 113.2, 122.6, 127.3, 132.0, 137.6, 146.1.
13
3
)
5
(31) Reagent quantities are representative of the 0.2 mol scale. Subsequent
reaction quantities were scaled accordingly.
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1
1
isolated yield, 96% purity) of N-phenylpiperidine. H and
(98% isolated yield, 98% purity) of N-phenylisoindoline. H
1
3
13
C NMR data are consistent with those found in the
literature.
Representative Example of the Scale-Up of Isoindo-
and C NMR data are consistent with those found in the
2
2,26,28,29
30
literature.
31
lines on a 0.2 mol Scale: Multimode Microwave Cavity.
Acknowledgment
To a 1 L round-bottom flask were added aniline (18.6 g, 0.2
mol), 1,2-bis(chloromethyl)benzene (38.6 g, 0.22 mol), and
potassium carbonate (32.5 g, 0.23 mol) in 400 mL of distilled
water. The reaction vessel was placed in a multimode micro-
wave reactor and fitted with a reflux condenser. The reaction
was irradiated with 300 W of power to a temperature of
The authors thank Dr. Rajender S. Varma from the U.S.
EPA for his ideas and support in this research as well as Dr.
Nicholas E. Leadbeater and the Leadbeater Research Group
from the University of Connecticut for obtaining the NMR
spectra of the synthesized compounds.
1
10 °C (reflux) where it was held for 20 min. Upon cooling,
Received for review August 17, 2006.
OP0601722
the solid product is filtered, washed with distilled water
followed by chilled hexanes, and dried in vacuo giving 38.3 g
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