Batch to flow deoxygenation using visible light photoredox catalysis

Article abstract of DOI:10.1039/c2cc37206a

Herein we report a one-pot deoxygenation protocol for primary and secondary alcohols developed via the combination of the Garegg-Samuelsson reaction, visible light-photoredox catalysis, and flow chemistry. This procedure is characterized by mild reaction conditions, easy-to-handle reactants and reagents, excellent functional group tolerance, and good yields.

Full text of DOI:10.1039/c2cc37206a

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Batch to flow deoxygenation using visible light
photoredox catalysis†‡
Cite this: Chem. Commun., 2013,
4
9, 4352
John D. Nguyen, Barbara Reiß, Chunhui Dai and Corey R. J. Stephenson*
Received 3rd October 2012,
Accepted 1st November 2012
DOI: 10.1039/c2cc37206a
www.rsc.org/chemcomm
Herein we report a one-pot deoxygenation protocol for primary
and secondary alcohols developed via the combination of the
Garegg–Samuelsson reaction, visible light-photoredox catalysis,
and flow chemistry. This procedure is characterized by mild reaction
conditions, easy-to-handle reactants and reagents, excellent functional
group tolerance, and good yields.
The deoxygenation of organic molecules is an important reaction
1
in organic synthesis, but remains one of the most difficult
transformations due to the bond strength of the carbon–oxygen
2
bond. The most well-known and commonly utilized radical
protocol for the removal of hydroxyl groups from alkyl alcohols
3
is the Barton–McCombie deoxygenation. Alternative methods
utilizing radical chemistry include benzoyl ester-mediated deoxy-
4
5
genations and phosphite-mediated deoxygenations (Scheme 1,
top). One aspect shared by all of the strategies mentioned above
involve activation of the hydroxyl group to an intermediate, such as
a xanthate, benzoate, or phosphite that can allow for a more facile
cleavage of the carbon–oxygen bond. Recently, Miller has reported
that phosphite-mediated deoxygenation can be utilized for mole-
6
cular editing via selective removal of hydroxyl groups from polyols
5b
such as erythromycin A. In an effort to develop a catalytic one-pot
process for the removal of hydroxyl groups operating under mild
conditions, we investigated the possibility of utilizing visible light
7,8
photoredox catalysis.
Recently, our laboratory has developed a visible light-
mediated technique for the conversion of primary and secondary
9
alcohols to alkyl bromides and iodides as well as a visible light-
Scheme 1 Conceptual goal toward catalytic visible light-mediated deoxygenation.
mediated method for the hydrodeiodination of alkyl, aryl, and
10
alkenyl iodides (Scheme 1, bottom). In principle, the combination
of these two reactions could be utilized to develop a visible light achieve a streamlined ‘‘dual’’ photocatalytic deoxygenation have
photoredox catalyzed one-pot deoxygenation in which the iodina- been unsuccessful largely due to the requirement for DMF in the
tion and the reduction reactions occurred sequentially without an iodination reaction, whereas the hydrodeiodination reaction is
intermediate work-up or purification. Thus far our attempts to sluggish in DMF, and competitive reduction of iodoform requiring
the use of much higher loading of electron donor/H-atom donor
reagents.
Department of Chemistry, Boston University, 590 Commonwealth Ave., Boston, MA,
However, the mild reaction conditions, functional group toler-
USA. E-mail: crjsteph@bu.edu; Fax: +1 617 353 2500; Tel: +1 617 358 5089
ance, and operational simplicity associated with photoredox catalysis
This article is part of the ChemComm ‘Emerging Investigators 2013’ themed issue.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cc37206a bolstered our effort to design a novel strategy for deoxygenation. Due
†
‡
4
352 Chem. Commun., 2013, 49, 4352--4354
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to the fact that the iodination procedure is more restricted in terms
In order to increase the efficiency of the reduction step we
of the reaction conditions, we explored alternative conditions for the decided to apply continuous flow chemistry based on the efficiency
13
conversion of alkyl alcohols to the alkyl iodides.
increase we observed in previous reports. Unfortunately, the
One of the most common methods for the conversion of alkyl presence of Hantzsch ester causes the reaction mixture to be
1
1
14
alcohols to alkyl iodides is the Garegg–Samuelsson reaction. In heterogeneous and unsuitable for our flow reactor. Therefore,
most cases, the addition of a primary or secondary alkyl alcohol, we decided to replace Hantzsch ester and tributylamine with
i
15
2
triphenylphosphine, imidazole, and iodine in a variety of solvents N,N-diisopropylethylamine ( Pr NEt) and include a small amount
efficiently converts alkyl alcohols to alkyl iodides with exceptional of MeOH to help homogenize the reaction mixture. A secondary
functional group tolerance. Therefore, we decided to investigate advantage of flow processing was that we had previously observed
whether this reaction could be combined with our hydrodeiodina- that catalyst loading could be lowered without loss of efficiency.
tion reaction. We envisioned the overall transformation would Therefore, the design of our protocol involves the formation of an
involve the conversion of the alkyl alcohol to the alkyl iodide and alkyl iodide in a batch reactor followed by the hydrodeiodination
subsequent addition of the photocatalyst, electron-donor/H-atom reaction performed in flow as shown in Scheme 2. Ultimately,
À1
donor reagents and light irradiation would cause reduction of the a flow rate of 75 mL min in a 1.34 mL reactor (approximately
carbon–iodide bond.
Our first step of this investigation involved finding a single
solvent that could be applied to both reactions to avoid an Table 1 One-pot deoxygenation of alkyl alcohols
intermediate work-up or solvent switch. Fortunately, the Garegg–
Samuelsson reaction has been reported to be efficient in dichloro-
a
b
Entry
Substrate
Product
Yield
12
methane, DMF, tetrahydrofuran, acetonitrile (MeCN), and toluene,
while the visible light-mediated hydrodeiodination reaction is
1
88
10
optimal in MeCN. With a common solvent in hand we began to
investigate the viability of developing a novel one-pot deoxygenation
protocol. Substrate 1 is fully converted to an alkyl iodide in 2 h
2
3
7
4
utilizing PPh
,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate) (2.0 equiv.), tri-
butylamine (2.0 equiv.), and fac-Ir(ppy) (1.0 mol%) is followed by
3
/I
2
/imidazole. The addition of Hantzsch ester (diethyl
81
1
3
4
5
8
8
7
5
0.5 h of degassing with argon and light irradiation. After 72 h the
reaction is incomplete and only a 50% conversion of the starting
material to 2 is observed.
6
7
7
0
8
7
8
Scheme 2 Schematic for visible light mediated one-pot deoxygenation protocol.
76
9
6
7
7
2
c
10
a
3
Reaction Conditions: alcohol (1.0 mmol), PPh (1.2–2.5 mmol),
I
2
(1.2–2.5 mmol), imidazole (1.2–5.0 mmol), MeCN (5.0–7.0 mL), fac-
i
Ir(ppy) (0.25–0.50 mol%), Pr NEt (10–15 mmol), MeOH (0.2–0.5 mL),
flow LED. % Isolated yield after chromatography on SiO
toluene (2.0 mL).
3
2
b
c
2
. With
Scheme 3 Increased efficiency of deoxygenation in a flow reactor.
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research fellowship. C.D. thanks AstraZeneca for a graduate
fellowship. NMR (CHE-0619339) and MS (CHE-0443618) facil-
ities at BU are supported by the NSF.
Notes and references
1
(a) R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH,
New York, 2nd edn, 1999, pp. 49–52; (b) G. E. Veitch, E. Beckmann,
B. J. Burke, A. Boyer, S. L. Maslen and S. V. Ley, Angew. Chem., Int.
Ed., 2007, 46, 7629–7632; (c) D. S. Palacios, T. M. Anderson and
M. D. Burke, J. Am. Chem. Soc., 2007, 129, 13804–13805.
Scheme 4 Advantages of visible light mediated one-pot deoxygenation protocol.
2
3
In Handbook of Chemistry and Physics, ed. W. M. Haynes, CRC Press,
an 18 minute residence time) with 0.25 mol% of fac-Ir(ppy)
without degassing) gave full conversion of 1 to the reduced
product 2 with an 88% isolated yield (Scheme 3, top). This
3
93rd edn, 2012.
(
(a) D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans.
1, 1975, 1574–1585; (b) D. Crich and L. Quintero, Chem. Rev., 1989,
8
9, 1413–1432; (c) D. L. J. Clive and J. Wang, J. Org. Chem., 2002, 67,
represents a 120 fold improvement to the conversion rate when
1192–1198.
1
6
compared to the same reaction in a batch reactor, which only
provided 75% conversion of 1 to 2 after 144 h (Scheme 3,
bottom).
4
(a) I. Saito, H. Ikehira, R. Kasatani, M. Watanabe and T. Matsuura,
J. Am. Chem. Soc., 1986, 108, 3115–3117; (b) K. Lam and I. E. Mark ´o ,
Org. Lett., 2008, 10, 2919–2922; (c) K. Lam and I. E. Mark ´o , Chem.
Commun., 2009, 95–97; (d) K. Lam and I. E. Mark ´o , Org. Lett., 2011,
The combination of the Garegg–Samuelsson reaction, visi-
ble light-photoredox catalysis, and flow chemistry was applied
successfully to the deoxygenation of a series of primary and
secondary alcohols (Table 1). The functional group tolerance of
this one-pot deoxygenation process is excellent with benzyl
ethers (entry 1), carbamates (entries 3 and 8), esters (entry 4),
cyclopropanes (entry 4), sulfonamides (entry 5), acetals (entry 6),
and distal olefins (entry 10) unaffected throughout both steps. In
the case of substrate 9, radical cyclization was observed rather
than simple reduction due to the highly favorable 5-exo-trig
cyclization (entry 5). In addition, primary alcohols can be
deoxygenated in the presence of secondary alcohols (entry 6)
by selectively iodinating the primary alcohol over the secondary
alcohol. Because the reduction step is tolerant of free alcohols,
the secondary alcohol is maintained throughout the one-pot
process. Overall, this strategy efficiently and mildly generates the
desired product with distinct advantages over other radical
deoxygenation procedures resulting from the combination of
photoredox catalysis and flow chemistry (Scheme 4).
1
3, 406–409.
5 (a) L. Zhang and M. Koreeda, J. Am. Chem. Soc., 2004, 126,
3190–13191; (b) P. A. Jordan and S. J. Miller, Angew. Chem., Int.
1
Ed., 2012, 51, 2907–2911.
For examples of molecular editing of complex molecules, see:
(a) A. M. Szpilman and E. M. Carreira, Angew. Chem., Int. Ed.,
6
2
010, 49, 9592–9628; (b) D. S. Palacios, I. Dailey, D. M. Siebert,
B. C. Wilcock and M. D. Burke, Proc. Natl. Acad. Sci. U. S. A., 2011,
08, 6733–6738.
7 For recent examples of the applications of photoredox catalysis, see:
1
(
(
(
a) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224–228;
b) Y. Ye and M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034–9037;
c) D. A. DiRocco and T. Rovis, J. Am. Chem. Soc., 2012, 134,
8094–8097; (d) C. J. Wallentin, J. D. Nguyen, P. Finkbeiner and
C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134, 8875–8884;
(
e) B. P. Fors and C. J. Hawker, Angew. Chem., Int. Ed., 2012, 51,
8
850–8853; ( f ) D. P. Hari, P. Schroll and B. K o¨ nig, J. Am. Chem. Soc.,
2012, 134, 2958–2961; (g) Z. Lu and T. P. Yoon, Angew. Chem., Int.
Ed., 2012, 51, 10329–10332.
8
For recent review of photoredox catalysis in synthetic applications,
see: (a) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev.,
2011, 40, 102–113; (b) F. Tepl ´y , Collect. Czech. Chem. Commun., 2011,
7
2
6, 859–917; (c) J. W. Tucker and C. R. J. Stephenson, J. Org. Chem.,
012, 77, 1617–1622; (d) J. Xuan and W.-J. Xiao, Angew. Chem., Int.
Ed., 2012, 51, 6828–6838.
9 C. Dai, J. M. R. Narayanam and C. R. J. Stephenson, Nat. Chem.,
011, 3, 140–145.
In conclusion, we have developed a catalytic one-pot deoxygena-
tion protocol for primary and secondary alcohols that is functional
group tolerant and can be performed under mild conditions. This
2
1
0 J. D. Nguyen, E. M. D’Amato, J. M. R. Narayanam and C. R. J.
Stephenson, Nat. Chem., 2012, 4, 854–859.
method consists of a Garegg–Samuelsson reaction to generate the 11 P. J. Garegg and B. J. Samuelsson, J. Chem. Soc., Chem. Commun.,
1
979, 978–980.
alkyl iodide from the primary or secondary alcohol, which is then
subjected to continuous flow under visible light irradiation in the
presence of fac-Ir(ppy) and N,N-diisopropylethylamine to effect a
3
hydrodeiodination. More importantly, this one-pot deoxygenation
protocol illustrates the advantages of combining photoredox
catalysis and flow chemistry, which include increased efficiency
and reduction of waste. Therefore, additional applications of
photoredox catalysis and flow chemistry are currently being
explored in our lab.
1
2 For examples, see: (a) P. J. Garegg, R. Johansson, C. Ortega and
B. J. Samuelsson, J. Chem. Soc., Perkin Trans. 1, 1982, 681–683;
(b) J. T. Starr, G. Koch and E. M. Carreira, J. Am. Chem. Soc., 2000,
1
22, 8793–8794; (c) J. M. G. Fern ´a ndez, A. Gadelle and J. Defaye,
Carbohydr. Res., 1994, 265, 249–269.
1
3 (a) F. R. Bou-Hamdan and P. H. Seeberger, Chem. Sci., 2012, 3,
1612–1616; (b) R. S. Andrews, J. J. Becker and M. R. Gagn ´e , Angew.
Chem., Int. Ed., 2012, 51, 4140–4143; (c) J. W. Tucker, Y. Zhang,
T. F. Jamison and C. R. J. Stephenson, Angew. Chem., Int. Ed., 2012,
51, 4144–4147; (d) M. Neumann and K. Zeitler, Org. Lett., 2012, 14,
2658–2661.
4 See ESI‡.
1
1
Financial support for this research from the NSF (CHE-
5 The use of NN-diisopropylethylamine as an electron donor/H-atom
donor reagent for photoredox catalyzed reductive dehalogenation
has been reported in the following reference: J. M. R. Narayanam,
J. W. Tucker and C. R. J. Stephenson, J. Am. Chem. Soc., 2009, 131,
1056568), the Alfred P. Sloan Foundation, Amgen, Boehringer
Ingelheim, and Boston University is gratefully acknowledged.
J.D.N. thanks AstraZeneca, The American Chemical Society
Division of Organic Chemistry and Amgen for graduate fellow-
ships. B.R. thanks the DAAD RISE Worldwide program for a
8756–8757.
1
6 The batch reactor set-up utilized is the same set-up described in
ref. 10.
4
354 Chem. Commun., 2013, 49, 4352--4354
This journal is c The Royal Society of Chemistry 2013