Expedient method for samarium(II) iodide preparation utilizing a flow approach

Article abstract of DOI:10.1055/s-0032-1317938

A facile method of SmIpreparation is presented which utilizes a continuous-flow system. The notoriously cumbersome handling and storage of the reagent can thus be avoided as appropriate amounts of SmIcan be conveniently prepared when needed. The method is illustrated and the reagent quality demonstrated by a series of typical SmIinduced transformations. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317938

394▌
LETTER
lEettxerpedient Method for Samarium(II) Iodide Preparation Utilizing a Flow
Approach
Samarium(II) Iodide Preparation under Flow Regime
Svatava Voltrova, Jiri Srogl*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague,
Czech Republic
E-mail: jsrogl@uochb.cas.cz
Received: 30.11.2012; Accepted after revision: 03.12.2012
In the present method, a solution of iodine source was
driven through a short heated column filled with samari-
um powder. After an initiation period consisting of in-
Abstract: A facile method of SmI preparation is presented which
utilizes a continuous-flow system. The notoriously cumbersome
handling and storage of the reagent can thus be avoided as appropri-
2
ate amounts of SmI can be conveniently prepared when needed. creasing the temperature to 185 °C for 15 minutes, the
2
The method is illustrated and the reagent quality demonstrated by a active, pitch dark blue reagent was continually formed at
8
series of typical SmI -induced transformations.
Efficiency of the preparation
2
an ambient temperature.
Key words: flow, samarium, samarium(II) iodide, reduction, re- was independently assessed by the following method: The
ductive coupling
reaction parameters – iodination reagent [(CH ) I , I ]
2
2 2
2
concentrations at the system input and output and the con-
centration of resulting samarium diiodide – were moni-
9
The synthetic role of samarium(II) iodide in organic syn- tored. Under the experimental conditions concentrations
thesis is undisputed. Due to the pioneering efforts of Ka- of the resulting SmI
(for the method see the experimental
section) and the corresponding incoming iodination re-
agent were virtually the same. Significantly, the concen-
2
gan,1 and later, Molander,2 SmI2 has become the
convenient reagent of choice in a great variety of diverse
3
reductive reactions. The wide synthetic applicability of
tration of SmI did not change due to the reaction course
2
SmI , which is derived from its unique reactivity patterns, (see Table 1 for details). The fact that the iodination re-
2
thus ranges from relatively simple sulfoxide reductions on agent is fully converted into the samarium diiodide offers
one side of the spectra to selective reductive cross-cou- an interesting possibility of the SmI
concentration con-
2
4
trol by altering the original amount of the iodination re-
pling reactions of carbonyl compounds on the other side.
1
0
Its more widespread use has been, however, hampered by agent. The process itself does not require extensive
cumbersome preparation and, due to its high reactivity, hardware control. Flow fluctuation caused by ongoing
5
even more difficult storage and handling. In the present size reduction of the Sm particles (ongoing reaction of sa-
study we want to report a convenient route for its prepara- marium in the cartridges) could be easily avoided by using
tion and demonstrate its efficacy in several model reac- only 50% of the theoretical amount of samarium before
tions.
periodical refilling of the cartridge. Under these condi-
tions no dramatic faltering of the pressure gradient or
blockage of the cartridge system was observed [for pa-
rameters of the process (pressure, Sm consumption) see
Table 1].
Encouraged by an onset of commercially accessible flow
systems, we wanted to utilize flow technology for prepar-
ing the samarium reagent. Based on the traditional synthe-
sis of metallic samarium treated by iodination reagent
4
6,7
such as 1,2-diiodoethane or iodine, a novel continual The efficacy of the SmI formation was demonstrated in a
2
preparation path has been developed (Figure 1). Besides variety of chemistries known to be mediated by the re-
5
the considerable convenience, the chief attributes of the agent (Scheme 1).
present preparative method are process scalability and re-
agent accessibility.
As shown in the control synthetic experiments, the present
protocol closely follows the previously published results
accomplished via standard procedures.
Overall, a new convenient way for the SmI preparation
2
was developed and the reactivity of the reagent examined
in a series of benchmark reactions. Letting aside the great
scalability inherent to a continuous flow regime, the chief
impact of the present preparative method lies in conve-
nient access to a very reactive reagent avoiding thus prob-
lematic storage and handling.
Figure 1 The outline of continuous preparation of SmI . Iodination
reagent is driven through the cartridge containing metallic samarium,
2
and the resulting SmI can be continually introduced to the substrate.
2
Continuous-flow reactions were performed on reactor X-Cube™
SYNLETT 2013, 24, 0394–0396
Advanced online publication: 21.12.2012
(ThalesNano Inc., Hungary; two CatCarts™ of 64 mm size, 4 mm
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
i.d. in series connection) or in home-made metal cartridges heater
DOI: 10.1055/s-0032-1317938; Art ID: ST-2012-D1020-L
Georg Thieme Verlag Stuttgart · New York
©

LETTER
Samarium(II) Iodide Preparation under Flow Regime
395
(
a) α-Diketone Formation7
a)
O
O
O
To benzoyl chloride (50.0 mg, 0.35 mmol) was dropped SmI solu-
2
SmI2
THF
tion (ca. 25 mL), and the reaction mixture was left at r.t. under argon
overnight. The blue color slowly changed to yellow. GC–MS anal-
ysis showed complete conversion of the starting compound. The re-
action mixture was poured to 5% HCl (20 mL) and extracted with
Et O (3 × 25 mL). The organic portion was washed with Na S O
solution and H O. After drying with MgSO , evaporation, and col-
umn chromatography (eluent hexane–Et O–acetone = 30:1:2), 1,2-
diphenylethanedione was obtained (25.7 mg, 70% yield; t = 11.09
min, m/z = 210.1; compared with the analytical standard). H NMR:
Cl
O
7
0%
b)
2
2
2
3
SmI2, H2O
THF
2
4
OH
2
4
R
8
7%
1
c)
d)
OH
δ = 7.97 m (4 H), 7.66 m (2 H), 7.52 m (4 H).
CHO
SmI2
THF
(
b) Ketone Reduction4
To the mixture of acetophenone (18 mg, 0.15 mmol) and MeOH
OH
3%
9
(9.6 mg, 0.30 mmol) was dropped SmI solution (ca. 10 mL, until
2
O
S
decoloration escaped). During 30 min standing at r.t. under argon,
the blue solution changed to yellow. GC–MS analysis showed com-
plete conversion of acetophenone. The reaction mixture was poured
SmI2
THF
S
to 5% HCl (20 mL) and extracted to Et O (3 × 30 mL). The organic
2
9
1%
portion was washed with Na S O solution and H O. After drying
2
2
3
2
e)
f)
with MgSO and evaporation, 1-phenylethanol was obtained (16
4
SmI2
THF
mg, 87% yield; t = 5.88 min, m/z = 122.0; compared with the ana-
R
1
lytical standard). H NMR: δ = 7.35–7.50 (m, 5 H), 5.00 (q, J = 6.4
Hz, 1 H), 2.27 (br s, 1 H), 1.62 (d, J = 6.4 Hz, 3 H).
O
9
4%
c) Pinacol Coupling7
(
O
D
O
To benzaldehyde (13.8 mg, 0.13 mmol) was dropped SmI solution
2
SmI2, D2O
THF
(
ca. 20 mL), and the reaction mixture was left overnight at r.t. under
O
O
argon, the blue solution changed to yellow. GC–MS analysis
showed complete conversion of the starting benzaldehyde. The re-
action mixture was poured to 5% HCl (20 mL) and extracted with
Et O (3 × 20 mL). The organic portion was washed with Na S O
D
9
3%
2
2
2
3
Scheme 1 Isolated yields of the benchmark synthetic reactions illus-
trating the effectivity of SmI generation: a) α-diketone formation, b)
ketone reduction, c) pinacol coupling, d) sulfoxide reduction, e) epox-
ide deoxygenation, f) olefine reduction.
solution and H O. After drying with MgSO , evaporation and col-
2
4
2
umn chromatography (eluent hexane–Et O–acetone = 30:1:2), 1,2-
2
4
diphenylethanediol was obtained (13 mg, 93% yield; t = 11.42
R
min, m/z = 214.1; compared with the analytical standard); mp
1
1
2
19.4–120.4 °C. H NMR: δ = 7.22 (m, 6 H), 7.13 (m, 4 H), 4.69 (s,
H), 2.98 (br s, 2 H).
(
Development Workshops, Institute of Organic Chemistry and Bio-
(d) Sulfoxide Reduction4
Diphenyl sulfoxide (20.2 mg, 0.1 mmol) was dissolved in THF (4
mL), and the solution was degassed (ultrasound, 10 min). To this
chemistry, Prague), on stainless steel cartridges of the same size.
Melting points were determined on a Stuart SMP 30 Melting Point
Apparatus and are not corrected. NMR spectra (δ, ppm; J, Hz) were
1
measured on Bruker Avance-400 instrument ( H NMR: 400 MHz)
solution was dropped SmI dissolved in THF (ca. 20 mL), and the
2
in CDCl and referenced to the solvent signal. Data are reported in
the following order: chemical shifts; multiplicities – indicated br
broadened), s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), app (apparent). GC analyses were performed on Agilent
GC–MS System (GC 7890A, inert MSD 5975C, Agilent Technolo-
gies). THF (containing 0.1% H O and 0.03% 2,6-di-tert-butyl-p-
cresol) was purchased from Penta, for titration procedures used as
received, for benchmark reactions distilled under atmospheric pres-
sure and dried over 4 Ǻ MS (H O content below 10 ppm; measured
by Karl Fischer Coulometer Mettler Toledo DL 32). Samarium
powder (ca. 40 mesh) was obtained from Strem Chemicals or from
Sigma-Aldrich, manipulated under open air and used without fur-
ther purification, reactants and other reagents were purchased from
Sigma-Aldrich or AlfaAesar and used as obtained.
reaction mixture was left 15 min at r.t. under argon, the blue solu-
tion changed to yellow. GC–MS analysis showed complete conver-
sion of the starting material. The reaction mixture was poured to 5%
3
(
HCl (20 mL) and extracted with Et O (3 × 20 mL). The organic por-
2
tion was washed with Na S O solution and H O. After drying with
2
2
3
2
3
2
MgSO and evaporation diphenyl sulfide was obtained (17 mg,
4
91% yield; t = 9.70 min, m/z = 186.0; compared with the analytical
R
1
standard). H NMR: δ = 7.22–7.32 (m, 10 H).
2
(
e) Epoxide Deoxygenation4
To trans-diphenyl-1,2-epoxyethane (19.6 mg; 0.1 mmol) was
dropped SmI solution (ca. 10 mL), and the reaction mixture was
2
left 30 min at r.t. under argon, the blue solution changed to yellow.
Both UPLC and GC–MS analysis showed complete conversion of
the starting material. The reaction mixture was poured to 5% HCl
Preparation of the Reagent for Test Reactions
(20 mL) and extracted with Et
2
O (3 × 25 mL). The organic portion
1
,2-Diiodoethane (2.6 g, 9.3 mmol) or iodine (2.3 g, 9.3 mmol)
was washed with Na S O solution and H O. Drying with MgSO ,
2
2
3
2
4
were dissolved in dry distilled THF (142 mL) and the solution de-
gassed by two freeze–pump–thaw cycles. Two CatCarts™ were
filled with samarium powder (2 × 0.7 g, 9.3 mmol) and heated to
evaporation and recrystallization from hexane afforded trans-
3
stilbene (17.0 mg, 94% yield; t = 10.39 min, m/z = 180.2; com-
R
1
pared with the analytical standard). H NMR: δ = 7.53 (m, 4 H),
185 °C for 15 min. After cooling, the iodination reagent solution
7.37 (m, 4 H), 7.27 (m, 2 H), 7.13 (s, 2 H).
was passed through the cartridges (r.t., flow rate 0.2–0.3 mL/min).
(
f) Olefine Reduction7
The dark-blue solution of SmI was dropped to tested reactants dis-
2
To ethyl cinnamate (100.0 mg, 0.56 mmol) was dropped SmI solu-
solved in degassed THF.
2
tion (ca. 50 mL), and the reaction mixture was left 30 min at r.t. un-
der argon. To the blue solution D O (0.1 mL, 5.5 mmol) was added,
2
and the blue color immediately changed to yellow. GC–MS analysis
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 394–396

396
S. Voltrova, J. Srogl
LETTER
showed complete conversion of the starting compound. The reac-
tion mixture was poured to 5% HCl (20 mL) and extracted with
Et O (3 × 25 mL). The organic portion was washed with Na S O
concentration of SmI solution was calculated from the ratio of cal-
2
ibrated areas of Tol S (t = 11.65 min, m/z = 214.2) to Tol SO (t =
2
R
2
R
13.22 min, m/z = 230.2; Table 1). All titrations were performed in
2
2
2
3
solution and H O. After drying with MgSO , evaporation, and col-
duplicate.
2
4
umn chromatography (eluent hexane–Et O–acetone = 30:1:2), ethyl
2
2
,3-dideuterio-3-phenylpropanoate was obtained (85 mg, 93%
yield; t = 8.09 min, m/z = 180.1; compared with the analytical stan- Acknowledgment
R
1
dard). H NMR: δ = 7.32 (m, 2 H), 7.26 (m, 2 H), 4.17 (q, J = 6.8
Hz, 2 H), 2.98 (m, 1 H), 2.65 (m, 1 H), 1.28 (t, J = 6.8 Hz, 3 H).
This work was supported by Ministry of Education of the Czech Re-
public (Grant LH12013).
Table 1 Concentration of SmI Prepared in Flowa
2
References and Notes
Entry Initial time SmI concn Pressure
Total Sm
2
gradient (bar) consumption (%)c
b
(
h)
(mol/L)
(1) Namy, J.-L.; Girard, P.; Kagan, H. B. New J. Chem. 1977, 1,
5
.
1
2
3
4
5
6
0
0.0507
0.0495
0.0493
0.0506
0.0495
0.0512
0.0486
0–1
0–1
0–1
0–1
1–2
2
1
7
(2) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
(
3) (a) Kagan, H. B. Tetrahedron 2003, 59, 10351. (b) Procter,
D. J.; Flowers, R. A.; Skrydstrup, T. Organic Synthesis
Using Samarium Diiodide. A Practical Guide; RSC
Publishing: Cambridge, 2010, ISBN: 978-1-84755-110-8.
4) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc.
0.5
1
13
37
49
97
95.4
(
3
1
980, 102, 2693.
4
(5) Typically, the reagent is prepared using the Schlenk
technique, and its quality varies depending on whether
remaining Sm metal is present in the resulting solution or
not. The reaction time in batch setting is much longer. See:
Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2012,
8
8d
7
–
a
7
7, 3049; and references cited therein.
Flow rate 0.2 mL/min, iodine concentration 0.05 mol/L, commer-
cially available wet THF used without degassing.
The backpressure of the X-Cube system.
Entries 1–6 are calculated values, entry based on iodination re-
(6) Imamoto, T.; Ono, M. Chem. Lett. 1987, 501.
(7) Concellón, J. M.; Rodríguez-Solla, H.; Bardales, E.; Huerta,
M. Eur. J. Org. Chem. 2003, 1775.
b
c
TM
agent. Entry 7 really consumed Sm after flow reaction.
Values of total collected reagent, volume 90 mL.
(8) After the reaction is successfully concluded and the substrate
d
is consumed the SmI addition (and preparation) can be
2
discontinued. New reaction can commence without any
further initiation procedure by starting the pumping process
again [(CH ) I or iodine solution]. The same cartridge can
be used in the multiple experiments until almost all the Sm
metal is depleted.
Titration Procedures
Two CatCarts™ were filled with samarium powder (2 × 0.75 g, 10.0
mmol), heated to 185 °C for 15 min and left to cool to 25 °C. Iodine
2
2 2
(
1.269 g, 5.0 mmol) dissolved in THF (100 mL) was passed through
(
9) For screening of the resulting reagent quality we developed
the titration method which reliably provides the active SmI2
molar concentration (see the experimental section).
the cartridges (r.t., flow rate 0.2 mL/min). At the time indicated in
Table 1 (Time 0 = start of SmI dropping, indicated visually), the
dark-blue solution of SmI (1 mL portion) was dropped to di(p-tol-
2
2
(
10) This may be true up to 0.13 M solution (solubility of SmI in
2
yl)sulfoxide (Tol SO, 23.0 mg, 0.1 mmol) dissolved in degassed
2
THF); see ref. 5.
THF (1 mL), left to decolorize (ca. 5 min), extracted with Et O, and
2
the ethereal solution after fitration was analyzed by GC–MS. The
Synlett 2013, 24, 394–396
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