A safe and reliable procedure for the iododeamination of aromatic and heteroaromatic amines in a continuous flow reactor

Article abstract of DOI:10.1016/j.tetlet.2009.10.007

A method for the safe and reliable iododeamination of aromatic and heteroaromatic amines under copper-free conditions is described and its scope is evaluated.

Full text of DOI:10.1016/j.tetlet.2009.10.007

Tetrahedron Letters 50 (2009) 7263–7267
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A safe and reliable procedure for the iododeamination of aromatic
and heteroaromatic amines in a continuous flow reactor
*
Laia Malet-Sanz , Julia Madrzak, Rhian S. Holvey, Toby Underwood
Research Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the safe and reliable iododeamination of aromatic and heteroaromatic amines under cop-
per-free conditions is described and its scope is evaluated.
Received 26 August 2009
Revised 24 September 2009
Accepted 2 October 2009
Available online 7 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Iododeamination
Diazo compounds
Flow chemistry
Alkyl nitrites
Continuous flow
Interest within the synthetic community in continuous flow
processes is rapidly increasing. Its advantages include precise con-
trol of the reaction variables, increased safety parameters and
ready scale-up of the reaction procedures.1 Flow methods thus al-
low highly reactive functionalities to be processed in a well-con-
trolled environment.2 It therefore represents an attractive option
for, amongst others, the pharmaceutical industry where safe, reli-
able and scalable processes are required.
The potential safety hazards associated with the formation and
use of diazonium intermediates are well documented.3 Their use in
industry requires extensive safety assessments and careful han-
dling. This becomes even more important as scale increases.
Although there are many examples of the use of diazonium inter-
mediates in certain industry sectors, the above considerations of-
ten result in higher processing costs or the development of
specialised reaction plants.4,5 Continuous flow methods for the for-
mation and in situ use of diazonium intermediates offer an attrac-
tive improvement.4,6 The reactive species are used as they are
formed and the total amount of material at each point of time is
strictly defined by the reactor volume. Reactor volumes in a contin-
uous flow can be significantly smaller than in batch although more
products can be obtained by simply flowing the system for a longer
period of time (time dependent scale-up) or by running several
reactors in parallel (scale-out).1 Furthermore, greater control of
the reaction variables that is, temperature, mixing and stoichiom-
etry, can be achieved in a flow reactor which can lead to improved
yields.7
de Mello and co-workers4 have previously published on a chlo-
rodeamination in continuous flow. Three aniline substrates were
reacted in a microreactor with isoamyl nitrite and CuCl2 to yield
the corresponding aryl chlorides. They demonstrated improved
yields compared with the corresponding batch procedures.
In this Letter, we describe a copper-free iododeamination per-
formed in continuous flow with good yields over a broad range
of substrates. The batch comparisons showed more by-product for-
mation, translating into lower overall isolated yields. The general
flow process has been shown to be readily scalable.
Iodides are very useful substrates for a variety of reactions,
including Suzuki–Miyaura, Negishi and Sonogashira couplings.8
We elected to use an anhydrous iododeamination protocol with al-
kyl nitrites as it was more attractive than the traditional aqueous
and acidic Sandmeyer conditions,9 which tend to form precipitates.
Precipitate formation is, in general, a problem in continuous flow
devices.1 Precipitates can form in the small channels of the reactors
or can be built-up in the pump heads and affect flow rate, or create
a complete blockage. For our experiments, we used the commer-
cially available Vapourtec R2+/R4 module10 and a 10 mL PFA loop
reactor (1 mm internal diameter). Therefore, we required condi-
tions that would keep the reaction homogeneous throughout the
sequence.
Treating anilines with alkyl nitrites under anhydrous and neu-
tral conditions are widely accepted to lead to the aryl radical upon
heating.11,12 Several mechanistic studies have shown that the reac-
tion does not proceed via a diazonium ion, as in the acidic and
aqueous Sandmeyer protocols,9,13 but via a triazene intermediate
(Scheme 1). It is believed that the triazene is again nitrosylated
and finally leads to the aryl radical.14
* Corresponding author. Tel.: +44 (0)1304 642065.
E-mail address: laia.malet@pfizer.com (L. Malet-Sanz).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.007

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L. Malet-Sanz et al. / Tetrahedron Letters 50 (2009) 7263–7267
N
H
NOH /OR
N
NH2
NH2
N
N
+
RONO
+
1,3-diphenyltriazene
.
RONO
ROH
N
N
N
O
N
N
N
N
N
O
benzenediazoanhydride
Scheme 1. Mechanism with alkyl nitrites under anhydrous conditions.
With this kind of protocol, an electron-transfer step from an
appropriate reducing agent such as a Cu(I) salt or others15 is not re-
quired. However, a ligand-transfer agent such as a Cu(II) salt16 may
still be required for the halogen transfer to take place. This ligand-
transfer step has been reported for metal-free species such as
CH2I214a and I211 for iododeaminations, and others including CHBr3
and CCl4 for bromo and chlorodeaminations, respectively.12 We
appreciated the advantages of a metal-free protocol on two fronts:
no metal residues would be present in the product and there would
be less probability of metal precipitates being formed. For example,
the Cu(II) salts and the CuO formed as a result of the reaction16 can
be difficult to solubilise if a solvent such as DMF is not used.4
Besides the high reactivity of all the reaction intermediates
(Scheme 1) and the nitrogen evolution, heating radical reactions
necessitate their own considerations of thermal hazards. Besides
the inherent temperature control possible with a flow reactor
due to its high surface to volume ratio,1 the functionality of the
Vapourtec R2+/R4 module (a safety cut-out pressure and an active
heating/cooling system by hot/cold air, respectively) allowed us a
very safe and controlled approach.
A study of the literature suggests that one of the best solvents to
stabilise the radical species formed would be acetonitrile,14b,16,17
and therefore we concentrated our efforts on using this solvent.
Other solvents such as DMF, THF and dioxane have been reported
as good hydrogen-transfer agents18 and hence those were avoided.
The initial optimisation experiments were carried out with a
substrate we were interested in, 2-amino-5-bromobenzonitrile 1
(Scheme 2). The first thing we looked at was the iodide source,
which had to be soluble in an organic solvent. Four were evaluated:
I2, n-Bu4NI, CH2I2 (neat and diluted with MeCN) and I2/KI (KI3).
Molecular iodine (known to be an excellent radical trap) in aceto-
nitrile produced the cleanest reaction and the product 5-bromo-2-
iodobenzonitrile 2 was easily purified.
Ar/Het NH2
MeCN
Bpr**
100 psi
5 mL 2 x 10 mL
0.2 mL/min
RT*
50 min
I2 (1.0 eq)
t-BuONO(1.5 eq)
MeCN
35 °C
12.5 min
ArI
0.2 mL/min
* RT = room temperature
** Bpr = back pressure regulator
aq. Na2S2O3
Figure 1. Initial reaction set-up for flow iododeamination.
The concentration of the starting material was determined by
the solubility of iodine in MeCN (up to 150 lM). Then, with an
equal flow rate in both pumps we could achieve a one to one
stoichiometry.
17c
The reported batch conditions
for substrate 1 included an
initial 10 min at 35 °C, followed by 1 h at room temperature.
With all this in mind, an initial flow set-up as per Figure 1 was
established. The amine substrate was flowed in anhydrous acetoni-
trile (150 lM) into a T-piece, where it was mixed with a second
Table 1
Synthesis of aryl iodides in a continuous flow reactor (set-up as in Fig. 1)
Entrya
Substrateb
Product
Yieldc (%)
Br
NH2
CN
Br
I
In all our experiments 1.5 equiv of t-BuONO was used11,16 and
the amount of iodine was kept at 1 mol equiv. Although some
authors17c have reported up to 3 equiv of iodine, excess iodine
can result in iodination by-products depending on the substrate
if excess t-BuONO is present.11 In turn, lack of iodine can increase
the ArH by-product.16
1
50
CN
1
NH2
CF3
I
Br
Br
2
3
52
46
CF3
3
Br
Br
I
NH2
I
NH2
CN
CN
t-BuONO, I source
MeCN
Br
Br
4
a
Br
1.0 equiv of I2, 1.5 equiv of t-BuONO, 1st loop at 35 °C (12.5 min residence time)
and 2nd loop at room temperature (50 min residence time).
All reagents and reactants were injected via 2 mL sample loops. Reactions were
performed on 0.3 mmol scale.
Br
b
1
2
c
Isolated yield.
Scheme 2. Initial optimisation.

L. Malet-Sanz et al. / Tetrahedron Letters 50 (2009) 7263–7267
7265
Table 2
stream containing iodine (150 lM) and t-BuONO (225 lM), also in
Synthesis of aryl and heteroaryl iodides in a continuous flow reactor (set-up as in Fig. 2)
anhydrous acetonitrile. The combined reagents were flowed at a
total flow rate of 0.4 mL/min into a first loop reactor with an inter-
nal volume of 5 mL at 35 °C (residence time of 12.5 min) and then
to a second loop reactor with a total volume of 20 mL (comprising
two 10 mL loops in sequence) at room temperature (residence time
of 50 min). The system was fitted with a back pressure regulator
(Bpr) of 100 psi. The collected stream was quenched into an aque-
ous solution of Na2S2O3 (Fig. 1). After extraction and purification by
flash column chromatography, the iodide product was isolated.
Substrates 1, 3 and 4 were evaluated using these conditions and
the results are described in Table 1.
When the reaction with substrate 3 was run using the same
conditions as per Figure 1, but having the iodine flowed in through
a third pump connected through a second T-Junction, immediately
after the aniline and the t-BuONO had been mixed in the first
T-Junction, resulted in a decreased 37% yield.
Entrya
Substrateb
Product
Yieldc (%)
1
91
NC
NH2
NC
I
I
NH2
2
81
NC
Br
NC
Br
NH2
NH2
I
3
4
66
60
CN
CN
I
Br
Br
At this point, and looking at other batch procedures16 we won-
dered if a reduced residence time and a higher temperature would
be more beneficial to the reaction outcome, as well as allowing a
higher product throughput (mg/min). We then designed a second
set-up with a single loop of 10 mL at 60 °C which with a combined
rate of 0.4 mL/min would give a residence time of 25 min (Fig. 2).19
Substrates 1, 3 and 4 were again evaluated and each gave slightly
higher yields of the corresponding iodide (Table 2, entries 3, 4 and
6). These conditions were then applied to a wider range of
substrates with good to moderate yields of products obtained
(Table 2).
CF3
Br
CF3
Br
NH2
I
5
6
51
63
nPr
Me
nPr
Me
Br
Br
Br
Br
NH2
I
Br
Br
The most common by-product identified was the diaryl-diazene
5 (Fig. 3). Phenolic by-product 6 and unreacted starting material
was not observed in any of the experiments.
NH2
t-Bu
I
7
8
5d
Substrates with an electron-withdrawing group in para (entry
1), meta (entry 2) or ortho (entries 3 and 4) positions, all gave high
yields. Despite the steric hindrance, anilines with bis-ortho-bromo
substitution (entries 5 and 6) gave reasonable 51% and 63% yields
of the respective iodides. Presumably there is a stabilising effect on
the aryl radical formed by the ortho-bromides. On the other hand,
very bulky groups in the ortho position, lacking electron-with-
drawing properties, such as t-butyl (entry 7) gave a very poor re-
sult. Smith et al.14a already noted the sensitivity of this
mechanism to steric hindrance, preventing the facile formation of
the triazene. For the electron-rich p-anisidine (entry 9) a moderate
43% yield was obtained. The more complex substrates of entries 11
and 12 gave 83% and 79% yields, respectively.
t-Bu
NH2
MeO
MeO
I
MeO
MeO
56
Cl
Cl
9
43
NH2
NH2
I
Me
O
Me
O
I
10
53f
In order to compare a representative batch and flow iododeam-
ination, the substrates from entries 1 and 3 (Table 2) were studied
in batch, using analogous conditions to those used in flow.20 4-
Iodobenzonitrile was isolated in 82% in batch yield after chroma-
tography, compared with the 91% yield obtained in the flow reac-
O
O
EtO
H2N
EtO
I
11
83
N
N
N
N
Ph
Ph
S
S
12e
13
79
51
NH2
I
N
N
I
Ar/Het NH2
NH2
MeCN
10 mL
Bpr* 100 psi
ArI
0.2 mL/min
N
Cl
N
Cl
a
1.0 equiv of I2, 1.5 equiv of t-BuONO, 60 °C with a residence time of 25 min.
All reactions were performed on 1.5 mmol scale, except entry 4 on 2.6 mmol
scale and entry 6 on 0.3 mmol scale. Reagents and reactants were entered through
the two top reagent inlets of the Vapourtec R2+.
b
60 °C, 25 min
I2 (1.0 eq)
t-BuONO(1.5 eq)
MeCN
c
All yields are isolated.
d
0.2 mL/min
Yield calculated from isolated material taking into account the by-product
present in the NMR spectrum.
e
Two loops of 10 mL were employed and a combined flow rate of 0.4 mL/min,
* Bpr = Back pressure regulator
aq. Na2S2O3
giving a residence time of 50 min.
f
Residence time of 50 min; 92% conversion. Note that a 35% isolated yield was
Figure 2. Final reaction set-up for flow iododeamination.
obtained with a 25 min residence time.

7266
L. Malet-Sanz et al. / Tetrahedron Letters 50 (2009) 7263–7267
Acknowledgements
R
We acknowledge the support received within Sandwich Chem-
N
istry Leadership Team for the realisation of this project. We would
like to thank Jonathan Fray, Andrew Mansfield, the ITC group at the
University of Cambridge, Duncan Miller, Alan Jessiman and Dafydd
Owen for their assistance and guidance.
N
OH
R
R
5
6
Supplementary data
Figure 3. Common by-products.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.007.
I
NH2
CN
1.5 eq t-BuONO
1.0 eq I2
References and notes
1. (a) Wiles, C.; Watts, P. Expert Opin. Drug Disc. 2007, 2, 1487–1503; (b) Geyer, K.;
Codée, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434–8442; (c) Mason, B.
P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007,
107, 2300–2318; (d) Styring, P.; Parracho, A. I. R. Beilstein J. Org. Chem. 2009, 5,
29.
MeCN, 60 °C
25 min
CN
91% (in flow)a
82% (in batch)
2. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. T.
Org. Biomol. Chem. 2008, 6, 1577–1586.
3. (a) Urben, P. G., 6th ed.. In Bretherick’s Handbook of Reactive Chemical hazards;
Butterworth Heinemann Ltd: Oxford, 1999; Vol. 2; (b) UK chemical reaction
hazards forum (CRHF): http://www.crhf.org.uk/incident12.html; http://
www.crhf.org.uk/incident71.html.; (c) Ullrich, R.; Grewer, T. Thermochim. Acta
1993, 225, 201–211; (d) Zollinger, H. In Supplement F2: The Chemistry of Amino,
Nitroso, Nitro and Related Groups; Patai, S., Ed.; John Wiley & Sons Ltd, 1996.
Chapter 13.
4. Fortt, R.; Wootton, R. C. R.; de Mello, A. J. Org. Process Res. Dev. 2003, 7,
762–776.
5. (a) Hodgson, H. H. Chem. Rev. 1947, 40, 251; (b) Doyle, W. H. J. Loss Prev. Process
Ind. 1969, 3, 14; (c) Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Process Res.
Dev. 2004, 8, 1059–1064; (d) Schroer, J. Eur. Pat. Appl. EP 827958 A1 19980311,
1998; Chem. Abstr. 1998, 128, 217230.
1.5 eq t-BuONO
1.0 eq I2
I
NH2
Br
CN
CN
MeCN, 60 °C
25 min
Br
66% (in flow)b
26% (in batch)
6. (a) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Lab Chip 2002, 2, 5–7; (b) Wootton,
R.; de Mello, A. J. Lab Chip 2002, 2, 7N–13N; (c) Jung, R.; Nickel, U.; Saitmacher,
K.; Unverdorben, L. U.S. Patent US 2001029294; Chem. Abstr. 2001, 135,
167969.; (d) Greenway, G. M.; Haswell, S. J.; Petsul, P. H. Anal. Chim. Acta 1999,
387, 1–10; (e) Salimi-Moosavi, H.; Tang, T.; Harrison, D. J. J. Am. Chem. Soc. 1997,
119, 8716–8717; (f) Roberge, D. M.; Zimmermann, B.; Rainone, F.; Gottsponer,
M.; Eyholzer, M.; Kockmann, N. Org. Process Res. Dev. 2008, 12, 905–910.
7. Schwalbe, T.; Autze, V.; Hohmann, M.; Stirner, W. Org. Process Res. Dev. 2004, 8,
440–454.
8. (a) Bissember, A. C.; Banwell, M. G. J. Org. Chem. 2009, 74, 4893–4895; (b)
Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 10, 1487; (c) Miyaura, N.;
Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437–3440; (d) Miyaura, N.;
Sukuki, A. Chem. Commun. 1979, 866–867; (e) Sonogashira, K.; Tohda, Y.;
Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470; (f) Negishi, E.; King, A. O.;
Okukado, N. J. Org. Chem. 1977, 42, 1821–1823.
a Entry 1, Table 2
b Entry 3, Table 2
Scheme 3. Representative batch comparison.
tion. 5-Bromo-2-iodobenzonitrile in batch was isolated in 26%
yield, compared with the 66% yield obtained in the flow reaction
(Scheme 3). In both cases the amount of by-product formation in-
creased, and in the latter case in a significant amount, as well as
having incomplete conversion of the starting material. We believe
the improvement achieved in flow is due to the high control of
reaction parameters that flow chemistry offers.
9. Galli, C. Chem. Rev. 1988, 88, 765–792.
10. www.vapourtec.co.uk.
The use of continuous flow allows reactions to be scaled up
safely and readily. To demonstrate this, we scaled the reaction with
4-aminobenzonitrile (entry 1, Table 1) up to 42 mmol from the ini-
tial 1.5 mmol. In order to increase the throughput, the flow rate
and the reactor volume was increased such that the residence time
remained unchanged. The reactor volume went from 10 to 40 mL
and the combined flow rate from 0.4 mL/min to 1.6 mL/min. The
amount of reactive intermediate in the reactor at one time was still
limited to 3 mmol. In total, 8.8 g of the desired 4-iodobenzonitrile
was obtained in 91% isolated yield. In addition, the material was all
processed in under 7 h.21
In conclusion, we have developed a reliable procedure for the
facile iododeamination of aromatic and heteroaromatic amines in
continuous flow. The high control of the reaction variables using
the flow technique significantly improved the yield over the corre-
sponding batch procedures. Combined with the advantages of the
continuous flow method for reaction scale-up (when exploiting
highly reactive intermediates) this makes this iododeamination
procedure of high synthetic utility and simple application. This
work opens the scope to further develop the formation and exploi-
tation of diazonium species in continuous flow processes. Work in
this direction is currently underway in our laboratories and will be
reported in due course.
11. Friedman, L.; Chlebowski, J. F. J. Org. Chem. 1968, 33, 1636–1638.
12. (a) Cadogan, J. I. G.; Roy, D. A.; Smith, D. M. J. Chem. Soc. 1966, 1249–1250; (b)
Beck, J. R.; Gajewski, R. P.; Lynch, M. P.; Wright, F. L. J. Heterocycl. Chem. 1987,
24, 267–270.
13. Sandmeyer, T. Chem. Ber. 1884, 17, 1633. 2650.
14. (a) Smith, W. B.; Chenpu Ho, O. J. Org. Chem. 1990, 55, 2543–2545; (b) Ku, H.;
Barrio, J. R. J. Org. Chem. 1981, 46, 5239–5241; (c) Cadogan, J. I. G.; Landells, R.
G. M.; Sharp, J. T. J. Chem. Soc., Perkin Trans. 1 1977, 1841–1843; (d) Paton, R.
M.; Weber, R. U. Org. Magn. Reson. 1977, 9, 494–496.
15. Galli, C. J. Chem. Soc., Perkin Trans. 2 1981, 1459–1461.
16. Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem. 1977, 42, 2426–2431.
17. (a) Liddle, B. J.; Gardinier, J. R. J. Org. Chem. 2007, 72, 9794–9797; (b)
Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S. J. Organomet. Chem. 2004, 689,
3810–3812; (c) Ek, F.; Wistrand, L. G.; Frejd, T. J. Org. Chem. 2003, 68, 1911–
1918.
18. Cadogan, J. I. G.; Molina, G. A. J. Chem. Soc., Perkin Trans. 1 1973, 541–542.
19. Representative flow procedure: The amine (1.5 mmol) was flowed in anhydrous
acetonitrile (150
lM) into a T-piece, where it was mixed with a second stream
containing iodine (1.5 mmol, 150
l
M) and t-butyl nitrite (2.3 mmol, 225 M),
l
also in anhydrous acetonitrile. The reagents were added through the top reagent
inlet of the Vapourtec and the valves were switched to the solvent position after
aspiration was complete. The combined reagents were flowed into a loop reactor
with an internal volume of 10 mL at 60 °C at a combined flow rate of 0.4 mL/min,
giving a residence time of 25 min. The system was fitted with a back pressure
regulator of 100 psi. Thecollected streamwas quenched intoan aqueous Na2S2O3
solution (20 mL) and was concentrated under reduced pressure to remove most
of the acetonitrile. Theaqueous phasewas extracted with EtOAc(4 Â 10 mL). The
combined organics were dried over MgSO4, filtered and concentrated under
reduced pressure to yield a solid. The solid was preloaded onto silica and purified

L. Malet-Sanz et al. / Tetrahedron Letters 50 (2009) 7263–7267
7267
by flash column chromatography with 40 g of silica and 0–10% of EtOAc in
heptane. Fractions bearing the product were combined and evaporated to yield
21. Scale-up flow procedure for 4-iodobenzonitrile: 4-Aminobenzonitrile (5.00 g,
42.3 mmol) was flowed in anhydrous acetonitrile (282 mL, 150 M) into a
T-piece, where it was mixed with a second stream containing iodine (10.7 g,
42.3 mmol, 150 M) and t-butyl nitrite (7.5 mL, 63.5 mmol, 225 M), also in
l
the corresponding iodide (see Table
1 for individual yields). Please see
Supplementary data for the analytical data.
l
l
20. Representative batch procedure. Batch reaction for 4-iodobenzonitrile (Table 2,
entry 1): t-Butyl nitrite (0.267 mL, 2.25 mmol) and iodine (381 mg, 1.5 mmol)
in anhydrous acetonitrile (10 mL) were added portionwise to a solution of 4-
aminobenzonitrile (177 mg, 1.5 mmol) in anhydrous acetonitrile (10 mL) at
room temperature. The mixture was heated at 60 °C for 25 min under a
nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was
added (20 mL) and the solution was concentrated under reduced pressure to
remove most of the acetonitrile. The aqueous phase was extracted with EtOAc
(4 Â 10 mL). The combined organics were dried over MgSO4, filtered and
concentrated under reduced pressure to yield a solid. The solid was preloaded
onto silica and purified by flash column chromatography with 40 g of silica and
0–10% of EtOAc in heptane. Fractions bearing product were combined and
evaporated to yield the product as a white solid (282 mg, 82%). 1H NMR (CDCl3,
400 MHz): d = 7.85 (d, 2H, 8.59 Hz), 7.37 (d, 2H, 8.59 Hz).
anhydrous acetonitrile (282 mL). The combined reagents were flowed into
four-loop reactors in line with individual internal volumes of 10 mL (total
volume of 40 mL) at 60 °C at a combined flow rate of 1.6 mL/min, giving a
residence time of 25 min. The system was fitted with a back pressure regulator
of 100 psi. The collected stream was quenched into an aqueous Na2S2O3
solution (500 mL) and was concentrated under reduced pressure to remove
most of the acetonitrile. The aqueous phase was extracted with EtOAc
(4 Â 250 mL). The combined organics were dried over MgSO4, filtered and
concentrated under reduced pressure to yield a brown solid. This solid was
dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced
pressure to yield the product as an off-white solid (8.77 g, 91%). 1H NMR
(CDCl3, 400 MHz): d = 7.85 (d, 2H, 8.59 Hz), 7.37 (d, 2H, 8.59 Hz).