Convenient in-flow preparation of Cr(II) chloride for Nozaki-Hiyama-Kishi reaction

Article abstract of DOI:10.1080/00397911.2015.1083580

A flow preparation of chromous chloride has been introduced as a viable alternative to the batch protocol. Activity of the prepared reagent has been demonstrated in the traditional Nozaki-Hiyama-Kishi reaction.

Full text of DOI:10.1080/00397911.2015.1083580

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Convenient In-Flow Preparation of Cr(II) Chloride
for Nozaki–Hiyama–Kishi Reaction
Svatava Voltrova & Jiri Srogl
To cite this article: Svatava Voltrova & Jiri Srogl (2015) Convenient In-Flow Preparation of Cr(II)
Chloride for Nozaki–Hiyama–Kishi Reaction, Synthetic Communications, 45:21, 2473-2477, DOI:
10.1080/00397911.2015.1083580
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1083580
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Date: 30 October 2015, At: 20:43

Synthetic Communications1, 45: 2473–2477, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1083580
CONVENIENT IN-FLOW PREPARATION OF Cr(II)
CHLORIDE FOR NOZAKI–HIYAMA–KISHI REACTION
Svatava Voltrova1 and Jiri Srogl1,2
1Institute of Organic Chemistry and Biochemistry, Academy of Sciences of
the Czech Republic, Prague, Czech Republic
2Department of Chemical and Biomolecular Engineering, North Carolina
State University, Raleigh, North Carolina, USA
GRAPHICAL ABSTRACT
Abstract A flow preparation of chromous chloride has been introduced as a viable
alternative to the batch protocol. Activity of the prepared reagent has been demonstrated
in the traditional Nozaki–Hiyama–Kishi reaction.
Keywords CrCl2; cross-coupling; flow; nickel; Nozaki–Hyiama–Kishi
INTRODUCTION
In the past several decades, the metal-mediated chemical transformation has
become a firm fixture in the toolbox of organic chemists. A great example is
metal-catalyzed cross-coupling reactions, which have evolved from an academically
fascinating topic into a real centerpiece of everyday synthetic work. This is true even
Received June 26, 2015.
Address correspondence to 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
2473

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S. VOLTROVA AND J. SROGL
Scheme 1. Nozaki–Hiyama–Kishi reaction.
though the overall requirements for using the synthetic protocols involving metals
are stringent; very often the success or failure of the desired transformation depends
solely on the control of the experimental setup, the quality of the solvent, and the
chemical environment.
A prime example of such a transformation is the Nozaki–Hiyama–Kishi
(NHK) reaction,[1] which, via a series of organometallic intermediates, connects
organic halogenides with aldehydes and leads to alcohols as the desired products
(Scheme 1). Although synthetically very useful, the reaction practicality has been
hampered by the following issue: To avoid problems with handling and storing
highly reactive CrCl2, the reagent has been commonly prepared in situ by reduction
of Cr3þ salts by Mn, Zn, complex hydrides and others.[1] As a consequence, however,
the witches’ brew of unreacted reducing chemical moieties, which have been present
in the reaction mixture, has often affected the reaction outcome.[1c]
DISCUSSION
Prompted by the issues associated with preparation, storing, and handling of
the chromous chloride, and encouraged by an onset of commercially accessible flow
systems we aimed to utilize the flow technology as the alternative platform for in-line
formation of the reagent.[2] In this study we want to report a convenient route for
CrCl2 preparation and demonstrate its efficacy in several model reactions. Among
other advantages,[3] the chief attributes of the present preparative method are process
scalability and reagent accessibility. A general procedure for the reductive formation
of CrCl2 was adopted from common batch protocols and transformed into a flow
version by using commercially available system (a cartridge-containing flow reactor
X-Cube®; see Fig. 1).
The method was further studied and optimized by altering parameters such as
expendable metal, temperature, cartridge filler, and flow-rate. Dimethylacetamide–
tetrahydrofuran (DMA-THF, 10:1) mixture has been employed as the solvent system
Figure 1. Outline of continuous preparation of CrCl2. Solvent is driven through the cartridge containing
finely powdered CrCl3, reducing metal (Zn or Mn), and alumina as a filler. The resulting CrCl2 can be
continually introduced to the substrate.

IN-FLOW PREPARATION OF Cr(II) CHLORIDE
2475
Table 1. Optimization of the Cr(III)-Cr(II) reduction inflowa
Activ.
Flow
Cr(II)
Al2O3 (g)
CrCl3 (g)
Red. metal (g)
temp. (°C)
(mL=min)
yield (%)
1
2
3
4
5
6
7
8
9
1.750
1.500
1.250
1.250
1.000
0
1.250
0.600
0
0.079
0.158
0.181
0.250
0.316
0.052
0.079
0.158
0.316
Zn, 0.300
Zn, 0.300
Zn, 0.600
Zn, 0.500
Zn, 0.600
Znb, 2.960
Mnc, 0.110
Mnc, 1.850
Mnc, 4.800
85
100
100
100
85
100
100
150
100
0.2
0.3
0.3
0.2
0.2
0.2
0.2
0.1
0.2
22.0
25.0
21.8
32.1
28.5
12.0
16.0
24.0
40.0d
aFor two cartridges (approx. vol. 1.6 mL, cartridges were filled up to 90% of their volume), solvent:
DMA-THF 10:1.
bGranular, particle size 0.2 mm.
cPowder, particles 325 mesh.
dMn reused after regeneration from the cartridge, yield of Cr(II) 20%.
of choice for its best chemical and physical properties. Results of the study are sum-
marized in Table 1.
To demonstrate a viability of the in-flow preparation method and the quality of
Cr2þ reagent, a solution of freshly formed CrCl2 was introduced to the series of
typical NHK substrates.[1c] The forte of the presently developed reagent preparation
has been exemplified by excellent isolated yields of the products (Table 2).
Improvement in the reaction control is yet another result of the new approach
to CrCl2 preparation. While it is not uncommon to use large excess of Cr precursors
in NHK synthetic applications (affecting detrimentally product isolation and overall
Table 2. Nozaki–Hiyama–Kishi reaction mediated by in-flow-generated CrCl2
R0
R
n(CrCl2) (mmol)
Time (h)
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
H
H
4-CH3
2-CO2CH3
2-CO2CH3
2-CO2CH3
2-CO2CH3
2-CO2CH3
2-CO2CH3
2-CO2CH3
C6H5
4-CH3-C6H4
C6H5
0.40
0.42
0.43
0.39
0.41
0.42
0.43
0.39
0.43
0.40
21
24
20
16
16
5
2
4
2
16
1a[5]
1b[6]
1b
80.3
90.4
89.8
86.2
80.4
92.4
88.3
65.2
94.3
76.7
C6H5
2a[7]
2b[8]
2c[8]
2d[9]
2e
4-CH3-C6H4
4-CH3O-C6H4
2-Cl-C6H4
4-CO2CH3-C6H4
3-Br-C6H4
C11H23
2f
2 g
10

2476
S. VOLTROVA AND J. SROGL
reaction efficacy),[4] we have successfully demonstrated that carefully measured
quantities suffice to facilitate the desired transformation.
EXPERIMENTAL
Generation of Chromium Dichloride
Al2O3 (neutral, particle size 0.05–0.15 mm, Brockmann activity I) and CrCl3
(sublimed) were ground with mortar and pestle until homogeneous (cca 1 min),
sieved (particle size 0.05 to 0.4 mm), mixed with the reduction metal, and packed into
the cartridges. After activation at the given temperature for 10 min, the flow was
turned on (solvent system DMA-THF 10:1), and the eluate (3 mL) was collected.
The content of Cr(II) was determined iodometrically.
Nozaki–Hiyama–Kishi Reaction, Typical Experiment
The solution of halogen derivative (0.15 mmol), aldehyde (0.2 mmol), and
NiCl2 (1 mg) in 1 mL DMA-THF 10:1 was degassed and treated with the eluate
(2.7 mL) obtained as described previously (row 4, Table 1). Progress of the reaction
was monitored with gas chromatography–mass spectrometry (GC-MS) or ultra-
performance liquid chromatography–mass spectrometry (UPLC-MS). After stirring
at 50 °C for the time given in Table 2, the green reaction mixture was diluted with
water (20 mL) and allowed to crystallize at rt (compounds 2a–2 g), or extracted with
ether (3 × 50 mL); the organic layer washed with brine (6 × 20 mL) and dried
with magnesium sulfate. The crystalline material resulting after evaporation was
recrystallized from ethanol (compounds 1a, 1b). The isolated yields and CrCl2
amounts are given in Table 2.
FUNDING
This work was supported by the Ministry of Education of the Czech Republic
(Grant No. LH12013).
SUPPLEMENTAL MATERIAL
1
Full experimental details, leaching and blind experiments, H and 13C NMR
spectra, and characterization of the compounds for this article can be accessed on
the publisher’s website.
REFERENCES
1. (a) Kishi, Y. Pure Appl. Chem. 1992, 64, 343–350; (b) Okude, Y.; Hirano, S.; Hiyama, T.;
Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179–3181. For the reviews see (c) Fürstner, A.
Chem. Rev. 1999, 99, 991–1045; (d) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1–36;
(e) Fürstner, A. Chem. Eur. J. 1998, 4, 567–570; (f) Takai, K. Org. React. 2004, 64,
253–612.
2. For conceptually similar inline preparation of sensitive metallic reagent SmI2 see Voltrova,
S.; Srogl, J. Synlett 2013, 24, 0394–0396.

IN-FLOW PREPARATION OF Cr(II) CHLORIDE
2477
3. Typically the reagent is prepared using Schlenk technique and its quality varies depending
on what remaining components are present in the resulting solution. For further details see
the review in Ref. 1(c).
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(b) Oddon, G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1157–1160.
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7. Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333–3336.
8. Mahmoodi, N. O.; Salehpour, M. J. Heterocycl. Chem. 2003, 40, 875–878.
9. Al-Hamdany, R.; Al-Rawi, J. M.; Ibrahim, S. J. Prakt. Chem. 1987, 329, 126–130.