Continuous flow coupling and decarboxylation reactions promoted by copper tubing

Article abstract of DOI:10.1021/ol1026848

A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, and decarboxylation reactions using a commercially available copper tube flow reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd), ligands, or reagents, and in greater than 90% yield in most cases examined.

Full text of DOI:10.1021/ol1026848

ORGANIC
LETTERS
2
011
Vol. 13, No. 2
80-283
Continuous Flow Coupling and
Decarboxylation Reactions Promoted by
Copper Tubing
2
†
Yun Zhang, Timothy F. Jamison, Sejal Patel,* and Nello Mainolfi*
‡
,†
,†
NoVartis Institutes for Biomedical Research Inc., Global DiscoVery Chemistry,
00 Technology Square, Cambridge, Massachusetts 02139, United States, and
1
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, United States
nello.mainolfi@noVartis.com;
sejal.patel@noVartis.com
Received November 8, 2010
ABSTRACT
A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, and decarboxylation reactions using a commercially
available copper tube flow reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd),
ligands, or reagents, and in greater than 90% yield in most cases examined.
In recent years organic synthesis has been impacted greatly
by the rapid growth of innovative technologies such as
the ability to perform reactions at high temperatures and high
pressures, and ease of scale-up. Many previously challenging
or hazardous reactions can now be safely and efficiently
1
microwave-assisted heating, polymer-supported reagents/
2
4
catalysts, and continuous flow processes. Among these
conducted in flow. In addition, flow synthesis methods can
developments, continuous flow chemical synthesis has
emerged as an important alternative to traditional batch
synthesis and enjoyed considerable use in both academic and
be combined with other enabling technologies to improve
efficiency and productivity significantly. As part of our
efforts to develop methods of chemical synthesis in flow,
5
3
industrial laboratories. Compared to batch, flow offers
several distinct benefits including efficient mixing, precisely
controlled reaction parameters, automated reaction processes,
(
4) Recent examples: (a) Bedore, M. W.; Zaborenko, N.; Jensen, K. F.;
Jamison, T. F. Org. Process Res. DeV. 2010, 14, 432. (b) O’Brien, M.;
Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596. (c) Grafton, M.;
Mansfield, A. C.; Fray, J. M. Tetrahedron Lett. 2010, 51, 1026. (d) Kulkarni,
A. A.; Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Org. Process Res. DeV.
2009, 13, 999. (e) Baumann, M.; Baxendale, I.; Martin, L. J.; Ley, S. V.
Tetrahedron 2009, 65, 6611. (f) Malet-Sanz, L.; Madrzak, J.; Holvey, R. S.;
Underwood, T. Tetrahedron Lett. 2009, 50, 7263.
†
Novartis Institutes for Biomedical Research.
Massachusetts Institute of Technology.
‡
(
(
(
1) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325.
2) Solinas, A.; Taddei, M. Synthesis 2007, 16, 2409.
3) Recent reviews: (a) Razzaq, T.; Kappe, O. C. Chem. Asian J. 2010,
(5) (a) Baxendale, I. R.; Hayward, J. J.; Ley, S. V. Comb. Chem. High
Throughput Screening 2007, 10, 802. (b) Bogdan, A. R.; Mason, B. P.;
Sylvester, K. T.; McQuade, T. D. Angew. Chem., Int. Ed. 2007, 46, 1698.
(c) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D.
Microreact. Org. Synth. Catal. 2008, 84. (d) Lee, J.-K.; Fuchter, M. J.;
Williamson, R. M.; Leeke, G. A.; Bush, E. J.; McConvey, I. F.; Saubern,
S.; Ryan, J. H.; Holmes, A. B. Chem. Commun. 2008, 39, 4780.
5
3
2
, 1274. (b) McMullen, J. P.; Jensen, K. F. Annu. ReV. Anal. Chem. 2010,
, 19. (c) Geyer, K.; Gustafsson, T.; Seeberger, P. H. Synlett 2009, 15,
382. (d) Jones, R. V.; Csajagi, C.; Szekelyhidi, Z.; Kovacs, I.; Borcsek,
B.; Urge, L.; Darvas, F. Chim. Oggi 2008, 26, 10. (e) LaPorte, T. L.; Wang,
C. Curr. Opin. Drug DiscoVery DeV. 2007, 10, 738. (f) Wild, G. P.; Wiles,
C.; Watts, P. Lett. Org. Chem. 2006, 3, 419.
10.1021/ol1026848  2011 American Chemical Society
Published on Web 12/08/2010

we now report a simple and expeditious means for conduct-
Our investigations began with the coupling of iodobenzene
(1a) and benzylamine (2a). After evaluating various condi-
tions in CTFR using the Vaportec R4/R2 system, we found
6
ing a variety of useful copper-promoted reactions using a
7
commercially available copper tube reactor.
1
1
The copper tube flow reactor (CTFR) that we employed
is made of a coil of copper tubing with 1.0 mm i.d. (inner
diameter) (Figure 1A). The coil is wound around an open
that with tetra-n-butylammonium acetate (TBAA) as base
1
0e
and acetonitrile as solvent, coupling of 1a and 2a was
achieved without the use of any other ligands or catalysts
(Table 1; see the Supporting Information for details). No
Table 1. Ullmann Coupling of 1a and 2a
residence flow rate conversion
a
b
entry
1
method
t (°C) time (min) (mL/min)
(%)
copper tube
copper tube
PFA tube
microwave
microwave
oil bath
150
150
150
150
150
90
30
120
30
0.33
0.17
0.33
65
100
0
50
31
40
Figure 1
.
(A) A copper flow coil. (B) A high-temperature CTFR
c
2
with the top metal jacket removed (1.0 mm i.d. tubing). (C) Heated
CTFRs using a standard Vaportec R4 heating module.
3
d
4
30
e
5
30
960
f
6
a
Flow conditions: 1a (2.0 mmol, 1.0 M), 2a (2.4 mmol, 1.2 M).
b
1
c
mesh support and, when inserted into a glass jacket, can be
heated by circulated air to 150 °C by using a standard
Vaportec R4 heating module. The copper tubing can be
heated safely up to 250 °C when a metal jacket is used
Conversion is based on H NMR analysis of crude materials. Two 10
d
mL CTFRs were connected in series. Microwave, 400 W, CuI (10 mol
e
%), CH CN (1.0 M). Microwave, 400 W, Cu powder (10 mol %), CH CN
3
3
f
(1.0 M). Sealed tube was used.
(
Figure 1, parts B and C). We envisioned that these reactors
would offer unique advantages of performing copper-
promoted reactions, i.e., by simply flowing substrates/
reagents into the heated coil without any additional catalysts
product formation was observed when the same conditions
were applied to experiments carried out in a PFA (perfluo-
roalkoxyalkane) tube reactor heated to the same temperature
(
copper or otherwise). Herein we report the first use of a
(entry 3), suggesting that the copper tubing was promoting
CTFR for Ullmann couplings (no added ligands), Sonogash-
ira couplings (no added Pd), and high-temperature protio-
decarboxylation reactions.
the reaction. Other parameters were then quickly tuned in
flow, and the optimal conditions are shown in entry 2. The
CTFR approach was more efficient than microwave and
batch reactions with traditionally used catalysts (entries 4-6).
Ullmann condensation of aryl halides and amines is a very
useful strategy to obtain aryl and biaryl N-containing
compounds, which occur in numerous natural products,
We then applied this protocol to couplings of several aryl
halides and amines. In general, a 250 psi backpressure
regulator was used to ensure that acetonitrile could be safely
heated well above its boiling point without flashing. The trace
8
pharmaceuticals, and polymers. The traditional conditions
used for this chemistry require high temperature, high copper
loading, and long reaction times. Spectacular improvements
have been made in the past decade, particularly rendering
the reaction conditions much milder by using suitable
12
amounts of copper leached from the tubing were efficiently
13
removed with Quadrapure Thiourea (QP-TU). As illustrated
in Table 2, both alkyl amines and N-containing heterocycles
were effective coupling partners. Reactions using less
reactive aryl bromides proceeded smoothly (entries 1 and
9
ligands. However, methods that do not use added ligands,
such as that described below, can generally be more
1
0
attractive.
6
). These conditions were also effective for the
1
4
Ullmann-Goldberg amide synthesis (entries 7 and 8).
(
6) Previous reports of copper flow technology: (a) Ceylan, S.; Klande,
T.; Vogt, C.; Friese, C.; Kirschning, A. Synlett 2010, 13, 2009. (b) Bogdan,
A. R.; Sach, N. W. AdV. Synth. Catal. 2009, 351, 849. (c) Bogdan, A. R.;
James, K. Chem.sEur. J. 2010ASAP.
(10) Selected examples (batch): (a) Truong, V.; Morrow, M. Tetrahedron
Lett. 2010, 51, 758. (b) Colacino, E.; Villebrun, L.; Martinez, J.; Lamaty,
F. Tetrahedron 2010, 66, 3730. (c) Zhang, J.; Zhang, Z.; Wang, Y.; Zheng,
X.; Wang, Z. Eur. J. Org. Chem. 2008, 30, 5112. (d) Yang, X.-D.; Li, L.;
Zhang, H.-B. HelV. Chim. Acta 2008, 91, 1435. (e) Zhu, R.; Xing, L.; Wang,
X.; Cheng, C.; Su, D.; Hua, Y. AdV. Synth. Catal. 2008, 350, 1253. (f)
Correaa, A.; Bolm, C. AdV. Synth. Catal. 2007, 349, 2673. (g) Zhao, Y.;
Wang, Y.; H.Sun, H.; Li, L.; Zhang, H. Chem. Commun. 2007, 3186.
(11) Yang, C.-T.; Fu, Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L.
Angew. Chem., Int. Ed. 2009, 48, 7398.
(
7) Copper tube flow reactors are available from Vapourtec Ltd.:
www.vapourtec.co.uk.
8) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Ullmann,
(
F. Ber. Dtsch. Chem. Ges. 1904, 37, 853. Reviews: (c) Lindley, J.
Tetrahedron 1984, 40, 1433. (d) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (e) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. 2009, 48, 6954. (f) Das, P.; Sharma, D.; Kumar,
M.; Singh, B. Curr. Org. Chem. 2010, 14, 754.
(
9) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13. (b) Ma,
D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (c) Ley, S. V.; Thomas, A. W.
Ang. Chem. Int. Ed. 2003, 42, 5400. (d) Kwong, F. Y.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2002, 4, 581.
(12) See the Supporting Information for trace copper analyses.
(13) QP-TU was purchased from Aldrich (product no. 655422).
(14) Goldberg, Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
Org. Lett., Vol. 13, No. 2, 2011
281

Table 2. Synthesis of Arylamines in CTFR
Table 3. Synthesis of Arylalkynes in CTFR
a
Reaction conditions: A solution of 1 (1.0 M), 4 (1.20 M) in DMF,
and a stock solution of TBAA (1.10 M) in DMF was mixed through pumps
b
into a T-mixer at a total flow rate of 0.33 mL/min. 0.50 mol %
Pd(PPh
3 2 2
) Cl was added, reaction was heated at 120 °C. The palladium
a
catalyst and leached trace amount of copper were removed with QP-TU.
Reaction conditions: A solution of 1 (1.0 M), 2 (1.20 M), and TBAA
c
1
d
Conversion is based on H NMR analysis of crude materials. Isolated
(
1.10 M) in CH
3
CN was injected from pump at 0.17 mL/min, two 10 mL
yields after flash chromatography on silica gel.
b
CTFR were connected using a standard PFA tubing (1.0 mm i.d.). 0.1
mL/min flow rate, 200 min residence time. Conversion is based on H
NMR analysis of crude materials. Isolated yields after flash chromatog-
c
1
d
raphy on silica gel.
served in any case, possibly attributable to the flow reaction
format (rate of alkyne addition and short residence time).
1
8
We also examined the use of high-temperature CTFR for
protiodecarboxylation reactions. Traditional batch processes
involve the use of copper powder or copper(I) salts at
Encouraged by the preliminary results, we next turned our
19
1
5
attention to the Sonogashira cross-coupling reaction,
16
particularly methods in which Pd was not used. After some
experimentation in heated CTFR, we learned that solvent
choice was a key paramter in flow. DMF was found to be
elevated temperatures and, in some cases, even above 250
20
°
2
C. Moreover, the release of CO gas generated in the
reaction at such temperatures raises significant safety con-
cerns, particularly when carrying out large scale syntheses
in batch. We speculated that flow reactors would provide us
with a more controlled process because only a small amount
of gas would be generated and liberated from the system at
any given time. As illustrated in Table 4, decarboxylation
reactions of many aromatic and heteroaromatic substrates
were successfully achieved at 250 °C in CTFR without any
additional catalysts, ligands, or additives. In the case of
5-fluoroindole-2-carboxylic acid, 2.0 equiv of quinoline and
longer reaction time were required (entry 6).
3
appropriate, but other solvents such as CH CN, THF, EtOAc,
and EtOH resulted in precipitation and subsequent system
blockage during the reaction. We found that TBAA, the
organic ionic base also used for the Ullmann-type reactions
(
vide supra), was again more effective than other commonly
used bases (e.g., Et N, H u¨ nig’s base, Et NH, n-BuNH ; see
3
2
2
the Supporting Information for details). A general protocol
was thus developed, and a range of arylalkynes were
constructed in good yields (Table 3). When less reactive
substrates such as bromobenzene (entry 1) or trimethylsilyl
acetylene (entry 5) were employed the reaction required a
catalytic amount of palladium. Notably Hay-Glaser cou-
(
17) (a) Hay, A. S. J. Org. Chem. 1960, 25, 1275. (b) Hay, A. S. J.
Org. Chem. 1962, 27, 3320. (c) Siemsen, P.; Livingston, R. C.; Diederich,
F. Angew. Chem., Int. Ed. 2000, 39, 2633.
1
7
pling byproducts (symmetrical 1,3-diynes) were not ob-
(
18) Slow addition of alkynes in a batch process: Thorand, S.; Krause,
N. J. Org. Chem. 1998, 63, 8551.
(
15) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
(19) Recent reports: (a) Goossen, L. J.; Rodriguez, N.; Linder, C.; Lange,
P.; Fromm, A. ChemCatChem 2010, 2, 430. (b) Goossen, L. J.; Manjolinho,
F.; Khan, B. A.; Rodriguez, N. J. Org. Chem. 2009, 74, 2620. (c) Goossen,
L. J.; Thiel, W. R.; Rodriguez, N.; Linder, C.; Melzer, B. AdV. Synth. Catal.
2007, 349, 2241.
1
2
975, 16, 4467. Recent reviews: (b) Chinchilla, R.; Najera, C. Chem. ReV.
007, 107, 874. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(
16) Selected examples (batch): (a) Jiang, H.; Fu, H.; Qiao, R.; Jiang,
Y.; Zhao, Y. Synthesis 2008, 15, 2417. (b) Monnier, F.; Turtaut, F.; Duroure,
L.; Taillefer, M. Org. Lett. 2008, 10, 3203. (c) Tambade, P. J.; Patil, Y. P.;
Nandurkar, N. S.; Bhanage, B. M. Synlett 2008, 6, 886. (d) Biffis, A.;
Scattolin, E.; Ravasio, N.; Zaccheria, F. Tetrahedron Lett. 2007, 48, 8761.
(20) (a) He, M.; Zhang, F. J. Org. Chem. 2007, 72, 442. (b) Molina, P.;
Fresneda, P. M.; Garcia-Zafra, G.; Almendros, P. Tetrahedron Lett. 1994,
35, 8851. (c) Atwell, G. J.; Baguley, B. C.; Denny, W. J. Med. Chem. 1989,
32, 396.
(
e) Chen, G.; Zhu, X.; Cai, J.; Wan, Y. Synth. Commun. 2007, 37, 1355.
282
Org. Lett., Vol. 13, No. 2, 2011

added Pd), and protiodecarboxylation reactions by way of a
simple and more environmentally benign procedure. The
reactor itself acts as a source of fresh copper metal and can
be safely heated at high temperatures and high pressures.
When experiments were performed under the same condi-
tions in PFA or stainless steel tube reactors, reactions failed
to give any desired products, suggesting a promoting effect
of the copper tubing. In many cases, the crude reaction
products can be used further in multistep processes without
additional purification.
Table 4. High-Temperature Protiodecarboxylation Reactions
Acknowledgment. The authors thank the NIBR Education
Office for a Presidential Postdoctoral Fellowship to Y.Z. and
Global Discovery Chemistry (GDC) for financial support.
The authors are grateful to Dr. Laetitia Martin (NIBR-Basel)
and Dr. Damien Webb (Massachusetts Institute of Technol-
ogy) for helpful discussions. The authors thank Ms. Penny
Wright (NIBR-Horsham) for trace copper analyses and the
analytical group at GDC-Cambridge for NMR spectroscopy
and HRMS assistance. The authors are indebted to Duncan
Guthrie, Chris Butters, and Adam Whyatt (Vapourtec Ltd.)
for useful suggestions and support.
a
Reaction conditions: A solution of 6 (1.0 M in NMP) was injected
b
c
1
from pump. Residence time. Isolated yields with purity >95% ( H NMR
spectroscopy). 2.0 equiv of quinoline was added; the experiment was set
d
up in recycling mode at 1.0 mL/min flow rate.
Supporting Information Available: Complete experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have demonstrated the effectiveness of
commercially available CTFR for several important copper-
mediated transformations including Ullmann condensations
(
no added supporting ligand), Sonogashira couplings (no
OL1026848
Org. Lett., Vol. 13, No. 2, 2011
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