Radical Deoxychlorination of Cesium Oxalates for the Synthesis of Alkyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.8b02045

A radical deoxychlorination of cesium oxalates has been developed for the preparation of hindered secondary and tertiary alkyl chlorides. The reaction tolerates a number of functional groups, including ketones, alcohols, and amides, and provides complementary reactivity to standard deoxychlorination reactions proceeding by heterolytic mechanisms. Preliminary studies demonstrate that the developed conditions can also be applied to deoxybromination and deoxyfluorination reactions.

Full text of DOI:10.1021/acs.orglett.8b02045

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical Deoxychlorination of Cesium Oxalates for the Synthesis of
Alkyl Chlorides
‡
Justin Y. Su,‡ Denise C. Grunenfelder, Kohei Takeuchi, and Sarah E. Reisman*
̈
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: A radical deoxychlorination of cesium oxalates has been
developed for the preparation of hindered secondary and tertiary alkyl
chlorides. The reaction tolerates a number of functional groups, including
ketones, alcohols, and amides, and provides complementary reactivity to
standard deoxychlorination reactions proceeding by heterolytic mechanisms.
Preliminary studies demonstrate that the developed conditions can also be
applied to deoxybromination and deoxyfluorination reactions.
Scheme 1. Radical Deoxychlorinations of Activated
Alcohols
lkyl chlorides are useful building blocks for organic
Asynthesis, and the chloride substituent is present in many
natural products and bioactive compounds.1,2 In the context of
fine chemical synthesis, this functionality is often introduced
by deoxychlorination of alcohols with reagents such as thionyl
chloride3 or CCl4/PPh3 (Appel conditions),4 which proceed
by polar mechanisms involving heterolytic cleavage of the C−
O bond.5,6 Depending on the substrate, these reactions can
proceed by either SN1 (3° alcohols) or SN2 (1° alcohols)
pathways. Hindered 2° alcohols (such as neopentyl alcohols)
are typically the most difficult substrates for deoxychlorination:
SN1 pathways can result in carbocation rearrangement and
competing elimination reactions, while SN2 pathways are
impeded by steric hindrance of the nucleophile trajectory. In
recent years, chemists have begun to address these limitations
by developing new reactions that afford alkyl chlorides via
reductive chlorination of ketones,7 C(sp3)−H chlorination,8
and hydrogen atom transfer-mediated olefin hydrochlorina-
tion9 and alkenyl chloride hydrogenation.10 Nonetheless, a
mild method for the radical deoxychlorination of hindered 2°
and 3° alcohols would provide a new tool for the preparation
of complex alkyl chlorides.
As part of a natural product synthesis effort, we required a
method to prepare a secondary neopentyl chloride. We
envisioned that a radical deoxychlorination could circumvent
some of the challenges presented by heterolytic deoxychlori-
nation, since chlorine atom transfer to a highly reactive carbon-
centered radical would likely be less sensitive to steric
encumbrance, while also avoiding counterion and aggregation
effects.11,12 The feasibility of radical deoxychlorination was first
established in 1975 by Jensen and Moder, who reported that
thermolysis of peroxyglyoxalates in the presence of CCl4
produced the corresponding alkyl chlorides (Scheme 1b).13
Subsequently, Crich and Fortt disclosed a related deoxychlori-
nation method using N-hydroxypyridine-2-thionyl oxalates as a
more practical activating group.14 In 1982, Cristol and Seapy
disclosed that photolysis of methyl xanthates with 254 nm light
in CCl4 also gives rise to C−Cl bond formation (Scheme
1c).15,16
While promising, these early methods suffer from modest
yields and limited substrate scope, which might result from the
•
formation of promiscuous CCl3 radicals that can lead to side
product formation. It was anticipated that catalytic generation
of carbon-centered radicals under mild conditions using visible
light could minimize nonproductive pathways and improve the
Received: June 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02045
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chlorination yield. Moreover, such methods would avoid the
formation of shock-sensitive peroxyglyoxalates and the use of
carbon tetrachloride, a carcinogen and ozone depleter.17 Here,
we report a radical deoxychlorination of cesium oxalates using
visible light photoredox catalysis (Scheme 1a), which enables
access to complex, hindered secondary and tertiary chlorides.
In our preliminary studies, the deoxychlorination of cesium
oxalate 1a was investigated with Ir[dF(CF3)ppy]2(dtbbpy)PF6
as a catalyst under irradiation with a blue light-emitting diode
(LED).18 A variety of chlorine atom sources and solvents were
examined, the results of which are summarized in Table 1.19
a
Table 1. Optimization of Reaction Conditions
a
b
entry
deviation from standard conditions
yield 2a (%)
1
2
3
4
5
6
7
8
none
82
32
17
0
75
20
36
34
72
0
NCS instead of ETCA
HCA instead of ETCA
3 instead of ETCA
4 instead of ETCA
MeCN instead of CH2Cl2
dioxane instead of CH2Cl2
THF instead of CH2Cl2
with 10 equiv H2O
no ETCA
9
10
11
12
no [Ir] catalyst
in dark
0
0
Figure 1. Substrate scope of radical deoxychlorination. Reactions
were conducted on 0.3 mmol scale. Isolated yields are reported.
Reactions for products 2a−j were run for 4 h; reactions for products
2k−o were run for 24 h. Chloride 2b was isolated in 92% yield as a
94:6 mixture of 2b to alkene side product as determined by 1H NMR.
Chloride 2e was isolated in 90% yield as a 92:8 mixture of 2e to
a
Reactions were conducted under inert atmosphere on 0.1 mmol
b
scale. Determined by 1H NMR versus pyrazine as an internal
standard.
1
alkene side products as determined by H NMR. Chloride 2h was
When ethyl 2,2,2-trichloroacetate (ETCA), a commercially
available and inexpensive reagent, was employed in CH2Cl2, 3°
chloride 2a was produced in 82% yield (entry 1).20 Use of N-
chlorosuccinimide (NCS) or 1,1,1,3,3,3-hexachloroacetone
(HCA) instead of ETCA delivered 2a in lower yields (entries
2 and 3), and when ethyl chloroacetate (3) was employed,
none of the chloride product was formed (entry 4). When
dimethyl 2,2-dichloromalonate (4)21 was used, chloride 2a was
obtained in 75% yield (entry 5); ultimately, ETCA was
selected as the chlorine atom source since it is more readily
available. Use of MeCN, dioxane, or THF as the solvent led to
a significantly diminished yield relative to CH2Cl2 (entries 6−
8). The addition of 10 equiv of water improved the solubility
of the oxalate 1a, but led to a slight decrease in yield (entry 9).
Control experiments in which ETCA, [Ir] catalyst, or light was
omitted confirmed that each of these components is necessary
for the reaction to proceed (entries 10−12).
Using the established protocol, we first examined the scope
of the reaction with several tertiary alcohol-derived cesium
oxalates (Figure 1). Cyclopentyl, cyclohexyl, and cycloheptyl
oxalates all performed well under the reaction conditions,
providing the corresponding chlorides in 67−87% yield
(entries 2b−g). For cyclohexyl substrate 1c, a 2.5:1 mixture
of diastereomeric oxalates was converged to chloride 2c with
greater than 9:1 dr,14b demonstrating that in certain contexts
radical deoxychlorination can be advantageous over reactions
that proceed through stereospecific mechanisms.22 The cesium
isolated in 54% yield as a 85:15 mixture of 2h to alkene side products
as determined by H NMR.
1
oxalate 1e, derived from the natural product (+)-sclareolide,
provided the corresponding alkyl chloride 2e in 83% yield. The
preparation of neopentyl 3° chloride 2h demonstrates the
ability of sterically encumbered oxalates to undergo the
chlorination. Oxalates derived from linalool oxide and a
benzoyl-protected piperidine delivered the tertiary chloride
products 2i and 2j, respectively, in moderate yield.
Secondary alcohol-derived substrates were found to react
under identical reaction conditions, but with longer reaction
times (24 h) required to achieve high conversions. The cesium
oxalates derived from (−)-thujone and (+)-isomenthol
provided the secondary alkyl chlorides 2k and 2l with high
diastereoselectivity (20:1 dr, Figure 1).23 Unsurprisingly, the
(−)-menthol-derived oxalate provided chloride 2m with only
modest diastereoselectivity (1.5:1 dr). Notably, chlorinations
of sterically demanding, bridged bicyclic ring systems (1n and
1o) were also enabled by the reaction conditions.24 A 1.3
mmol scale procedure in which 1l was prepared and subjected
directly to the chlorination conditions delivered 2l in 65%
overall yield.
To further probe the functional group tolerance of the
reaction, we investigated how the addition of exogenous
molecules bearing functional groups impacted the conversion
B
DOI: 10.1021/acs.orglett.8b02045
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of cesium oxalate 1l to secondary chloride 2l (Figure 2).25 The
reaction proceeded without significant reduction in yield in the
Table 2. Comparison with Nonradical Deoxychlorination
Processes
a
Figure 2. Functional group tolerance of the radical deoxychloriantion.
Reactions were conducted on 0.1 mmol scale. Values in parentheses
are % of additive remaining. Yields and additive recovery were
determined by GC relative to an internal standard.
presence of a ketone, alcohol, alkyl bromide, benzofuran, or
pyridine, and the respective additives were recovered in good
yields. The reaction also proceeded in the presence of a
terminal alkene and imidazole; however, these additives were
consumed to a greater extent. The reaction was inhibited by 3-
tert-butylphenol and 1,2,2,6,6-pentamethylpiperidine, and
these additives were consumed. It is likely that, under the
reaction conditions, the tertiary amine was oxidized by the
excited state [Ir] catalyst.
To provide a comparison with more conventional heterolytic
deoxychlorination processes, we evaluated a subset of the
alcohol substrates from Figure 1 under standard thionyl
chloride and Appel reaction conditions (Table 2). For the 3°
alcohols 1a-OH, 1e-OH, and 1h-OH, the radical deoxychlori-
nation conditions gave improved results overall relative to the
use of thionyl chloride; in particular, a decrease in the
formation of alkenes resulting from competitive E1 pathways
was observed (entries 1−3, method B). For example, the
SOCl2-mediated chlorination of sclareolide-derived alcohol 1e-
OH produced chloride 2e in only 45% yield; the mass balance
is a mixture of alkene isomers (6, 55% yield, entry 2). A similar
reaction outcome was observed for adamantyl-derived alcohol
1h-OH, with SOCl2 delivering chloride 2h in 51% yield and
41% yield of alkene isomers 7 (entry 3). In contrast, the radical
deoxychlorination conditions (method A) only gave an 8%
yield of alkenes 7, allowing for easier chromatographic
purification of chloride 2h. Unsurprisingly, no chlorination of
the 3° alcohols was observed under traditional Appel
conditions (method C).
For secondary alcohols 1l-OH and 1n-OH, thionyl chloride
afforded poor yields of the corresponding chlorides (entries 4−
5, method B). Under the Appel conditions (method C),
(+)-isomenthol (1l-OH) predominantly underwent elimina-
tion to cyclohexene 8 (entry 4).26 The relatively hindered
framework of (+)-fenchol (1n-OH) gave chloride 2n in 63%
yield using method C; however, rearrangement also occurred
to give α-fenchene (9) in 21% yield (entry 5). Subjection of
oxabicycle 1o-OH to either SOCl2 or Appel conditions
a
Reactions were conducted on 0.1 mmol scale. Yields determined by
1H NMR analysis of the crude reaction mixture using pyrazine as an
internal standard.
delivered a ∼1:1 mixture of chloride 2o and rearranged
chloride 10 in near-quantitative yield (entry 6).27 This
reactivity study demonstrates an advantage of the radical
deoxychlorination developed here, which minimized the
formation of elimination and rearrangement products and
consistently delivered the chloride across a range of secondary
and tertiary oxalates.
Although the primary focus of this study was the
development of radical deoxychlorination reactions, prelimi-
nary investigations reveal that these conditions can be adapted
for deoxybromination and deoxyfluorination.28,29 When diethyl
bromomalonate was used in place of ETCA, the alkyl bromides
were obtained (Figure 3). For these reactions, addition of 0.5
equiv of Cs2CO3 was found to improve the yield of the
bromide product. Alternatively, use of Selectfluor as the halide
source provided the corresponding alkyl fluorides, although the
yields were generally lower. These findings show the flexibility
of this deoxyhalogenation approach to prepare the alkyl
chlorides, bromides, or fluorides.
In conclusion, a method for radical deoxychlorination of
cesium oxalates under photoredox catalysis has been
C
DOI: 10.1021/acs.orglett.8b02045
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Scott Virgil and the Caltech Center for Catalysis
and Chemical Synthesis for access to analytical equipment. We
also thank Nicholas J. Fastuca for assistance in substrate
preparation and Dr. Matthew J. Hesse for helpful discussions
(both of Caltech). Fellowship support was provided by the
National Science Foundation (graduate research fellowship to
D.C.G., Grant No. DGE-1144469). S.E.R. is an American
Cancer Society Research Scholar and Heritage Medical
Research Institute Investigator. Financial support from the
NSF (CAREER-1057143) is gratefully acknowledged.
REFERENCES
■
(1) (a) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
̈
10693−10697. (b) Samann, C.; Dhayalan, V.; Schreiner, P. R.;
Knochel, P. Org. Lett. 2014, 16, 2418−2421. (c) Atack, T. C.; Cook,
S. P. J. Am. Chem. Soc. 2016, 138, 6139−6142.
(2) (a) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141−152.
́
(b) Gribble, G. W. Environ. Chem. 2015, 12, 396−405. (c) Gal, B.;
Figure 3. Radical deoxybromination and deoxyfluorination. Reactions
were conducted on 0.3 mmol scale with 1.5 equiv of halide source in
CH2Cl2. Reactions for products 11a−c and 12a−c were run for 4 h;
reactions for products 11d and 12d were run for 24 h. Isolated yields
are reported. Reaction for 12d was performed in CD2Cl2, and the
yield was determined by 1H NMR analysis of the crude reaction
mixture using pyrazine as an internal standard.
Bucher, C.; Burns, N. Z. Mar. Drugs 2016, 14, 206.
(3) (a) Darzens, G. Acad. Sci., Paris, C. R. 1911, 152, 1314−1317.
(b) Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc. 1952, 74, 308−311.
(c) Davis, M.; Skuta, H.; Krubsack, A. J. Mech. React. Sulfur Compd.
1970, 5, 1−57.
(4) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801−811.
(5) Chung, W.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2016, 55,
4396−4434.
(6) Additional deoxychlorination reactions: (a) Kozikowski, A. P.;
Lee, J. Tetrahedron Lett. 1988, 29, 3053−3056. (b) Bendall, J. G.;
Payne, A. N.; Screen, T. E. O.; Holmes, A. B. Chem. Commun. 1997,
1067−1068. (c) Li, Z.; Crosignani, S.; Linclau, B. Tetrahedron Lett.
2003, 44, 8143−8147. (d) Ortega, N.; Feher-Voelger, A.; Brovetto,
developed. The reactions proceed at room temperature with
visible light, and ethyl trichloroacetate was identified as an
effective and readily available chlorine atom source. A
comparison study of the radical deoxychlorination reaction
with thionyl chloride and Appel reaction conditions demon-
strated a diminished propensity for rearrangements and
elimination processes compared to the nucleophilic substitu-
tion-based chemistry. The conditions were successfully
translated to the synthesis of alkyl bromides and fluorides by
using diethyl bromomalonate or Selectfluor, respectively.
Efforts in our laboratory directed toward continued develop-
ment and implementation of this transformation in natural
product synthesis are ongoing.
́
M.; Padron, J. I.; Martín, V. S.; Martín, T. Adv. Synth. Catal. 2011,
353, 963−972. (e) Azad, C. S.; Saxena, A. K. Tetrahedron 2013, 69,
2608−2612.
(7) Reyes, J. R.; Rawal, V. H. Angew. Chem., Int. Ed. 2016, 55, 3077−
3080.
̈
(8) (a) Quinn, R. K.; Konst, Z. A.; Michalak, S. E.; Schmidt, Y.;
Szklarski, A. R.; Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C.
D.; Alexanian, E. J. J. Am. Chem. Soc. 2016, 138, 696−702. (b) Qin,
Q.; Yu, S. Org. Lett. 2015, 17, 1894−1897. (c) Xiong, H.-Y.; Cahard,
D.; Pannecoucke, X.; Besset, T. Eur. J. Org. Chem. 2016, 2016, 3625−
3630. (d) Ozawa, J.; Kanai, M. Org. Lett. 2017, 19, 1430−1433.
(e) Combe, S. H.; Hosseini, A.; Parra, A.; Schreiner, P. R. J. Org.
Chem. 2017, 82, 2407−2413. (f) Han, L.; Xia, J.-B.; You, L.; Chen, C.
Tetrahedron 2017, 73, 3696−3701. (g) Zhao, M.; Lu, W. Org. Lett.
2017, 19, 4560−4563. (h) Short, M. A.; Blackburn, J. M.; Roizen, J. L.
Angew. Chem., Int. Ed. 2018, 57, 296−299. (i) Li, G.; Dilger, A. K.;
Cheng, P. T.; Ewing, W. R.; Groves, J. T. Angew. Chem., Int. Ed. 2018,
57, 1251−1255.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02045.
(9) (a) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47,
5758−5760. (b) Wilger, D. J.; Grandjean, J.-M. M.; Lammert, T. R.;
Nicewicz, D. A. Nat. Chem. 2014, 6, 720−726. (c) For a review on
the subject, see: Crossley, S. W. M.; Obradors, C.; Martinez, R. M.;
Shenvi, R. A. Chem. Rev. 2016, 116, 8912−9000.
(10) (a) King, S. M.; Calandra, N. A.; Herzon, S. B. Angew. Chem.,
Int. Ed. 2013, 52, 3642−3645. (b) King, S. M.; Ma, X.; Herzon, S. B.
J. Am. Chem. Soc. 2014, 136, 6884−6887.
(11) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91,
1237−1286.
(12) Methods for radical decarboxyhalogenation: (a) Johnson, R. G.;
Ingham, R. K. Chem. Rev. 1956, 56, 219−269. (b) Kochi, J. K. J. Am.
Chem. Soc. 1965, 87, 2500−2502. (c) Barton, D. H. R.; Crich, D.;
Motherwell, W. B. Tetrahedron Lett. 1983, 24, 4979−4982. (d) Starr,
Detailed experimental procedures, compound character-
1
ization data, H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: reisman@caltech.edu.
ORCID
Justin Y. Su: 0000-0002-1946-3908
Sarah E. Reisman: 0000-0001-8244-9300
Author Contributions
‡J.Y.S. and D.C.G. contributed equally.
D
DOI: 10.1021/acs.orglett.8b02045
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 8793−
8794. (e) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am. Chem.
Soc. 2012, 134, 4258−4263. (f) Ventre, S.; Petronijevic, F. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 5654−5657.
́
́
(g) Candish, L.; Standley, E. A.; Gomez-Suarez, A.; Mukherjee, S.;
Glorius, F. Chem. - Eur. J. 2016, 22, 9971−9974.
(13) Jensen, F. R.; Moder, T. I. J. Am. Chem. Soc. 1975, 97, 2281−
2283.
(14) (a) Crich, D.; Fortt, S. M. Synthesis 1987, 1987, 35−37. (b)
Investigation of the diastereoselectivity of radical halogenation in
cyclohexyl substrates: Damm, W.; Giese, B.; Hartung, J.; Hasskerl, T.;
Houk, K. N.; Hu
4079.
̈
ter, O.; Zipse, H. J. Am. Chem. Soc. 1992, 114, 4067−
(15) Cristol, S. J.; Seapy, D. G. J. Org. Chem. 1982, 47, 132−136.
(16) Application of radical deoxyhalogenation in pentagonal
dodecahedranes: Landenberger, P.; Scheumann, K.; Keller, M.;
̈
Hunkler, D.; Fritz, H.; Worth, J.; Knothe, L.; Prinzbach, H. J. Org.
Chem. 2001, 66, 5744−5758.
(17) While dichloromethane is also considered “undesirable,” it is
the halogenated solvent of choice when one is required: Alfonsi, K.;
Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine,
H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green
Chem. 2008, 10, 31−36.
(18) (a) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am.
Chem. Soc. 2013, 135, 15342−15345. (b) Nawrat, C. C.; Jamison, C.
R.; Slutskyy, Y.; MacMillan, D. W. C.; Overman, L. E. J. Am. Chem.
Soc. 2015, 137, 11270−11273. (c) Zhang, X.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2016, 138, 13862−13865.
(19) Reactions conducted using a Hepatochem EvoluChemTM
PhotoRedOx Box device with a built-in cooling fan.
(20) Ethyl trichloroacetate was distilled prior to use; residual HCl
neutralizes the oxalate salt and decreases the yield.
(21) Prepared from dimethyl malonate according to the following
reference: Zhang, Y.; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 15038−15039.
(22) Separation of the two diastereomers of 1c, and independent
subjection of each to the reaction conditions, results in formation of
2c with identical diastereoselectivity.
(23) The reductive ketone deoxychlorination developed by Rawal
and co-workers provides the opposite diastereomer of 2k, which
demonstrates the complementarity of the two methods (see ref 7).
(24) Although the mass balance of this reaction is modest, significant
formation of alkene, rearrangement, or proto-deoxygenated side
1
products is not detected by H NMR analysis.
(25) (a) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597−601.
(b) Collins, K. D.; Ru
1348−1353.
̈
hling, A.; Glorius, F. Nat. Protoc. 2014, 9,
(26) Chlorination of the corresponding xanthate with SO2Cl2 under
the conditions developed by Kozikowski and Lee proceeds in 76%
yield. See ref 6a.
(27) The formation of 10 likely occurs by neighboring group
participation of the proximal ether oxygen to form the oxocarbenium,
followed by addition of chloride to the adjacent carbon center.
Carman, R. M.; Fletcher, M. T. Aust. J. Chem. 1983, 36, 1483−1493.
(28) A radical deoxybromination of xanthates was developed for a
synthesis of aplydactone: Meier, R.; Trauner, D. Angew. Chem., Int. Ed.
2016, 55, 11251−11255.
(29) See Supporting Information for evaluation of additional
bromine atom sources.
E
DOI: 10.1021/acs.orglett.8b02045
Org. Lett. XXXX, XXX, XXX−XXX