Sulfamate Esters Guide Selective Radical-Mediated Chlorination of Aliphatic C?H Bonds

Article abstract of DOI:10.1002/anie.201710322

Masked alcohols are particularly appealing as directing groups because of the ubiquity of hydroxy groups in organic small molecules. Herein, we disclose a general strategy for aliphatic γ-C(sp³)?H functionalization guided by a masked alcohol. Specifically, we determine that sulfamate ester derived nitrogen-centered radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to guide γ-C(sp³)?H chlorination. This reaction proceeds through a light-initiated radical chain-propagation process and is capable of installing chlorine atoms at primary, secondary, and tertiary centers.

Full text of DOI:10.1002/anie.201710322

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Sulfamate Esters Guide Selective Radical-Mediated Chlorination
of Aliphatic C-H Bonds.
Authors: Melanie A Short, J Miles Blackburn, and Jennifer L Roizen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710322
Angew. Chem. 10.1002/ange.201710322
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10.1002/anie.201710322
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COMMUNICATION
Sulfamate Esters Guide Selective Radical-Mediated Chlorination
of Aliphatic C–H Bonds
Melanie A. Short,[a],[+] J. Miles Blackburn,[a],[+] and Jennifer L. Roizen*[a]
Abstract: Masked alcohols are particularly appealing as directing
groups because of the ubiquity of hydroxyl groups in organic small
molecules. Herein, we disclose a general strategy for aliphatic γ-
C(sp3)–H functionalization guided by a masked alcohol. Specifically,
we determine that sulfamate ester-derived nitrogen-centered
radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to
guide γ-C(sp3)–H chlorination. This reaction proceeds through a
light-initiated radical chain-propagation process and is capable of
installing chlorine atoms at primary, secondary, and tertiary centers.
chlorination methods,[19]
chlorination processes.
or site-selective intermolecular[20]
O
(A) Innate Selectivity
Vanderwaal, Alexanian
and co-workers
F3C
tBu
N
Cl
hν
Cl
Ph
O
Ph
O
Cs2CO3
CF3
S
Me
ω
S
Me
δ
β
β
δ
α
α
γ
γ
ω
O
O
O O
PhH, 55 °C
δ-isomer: 56.2% of product
γ-isomer: 16.2% of product
(86% combined yield of
α,β,γ,δ,ω isomers)
functionalization[1]
facilitates
(B) γ-Selective (These Investigations)
Cl
Late-stage
alkyl
C–H
investigations into pharmaceutical small molecule leads.[2]
Unfortunately, position-selective reactivity is difficult to achieve
at unactivated C(sp3)–H centers, which have high bond
dissociation energies (90–105 kcal/mol), are not acidic (pKa ≥
50), and do not integrate more polarizable and electronically
accessible π-orbitals. Consequently, in most efficient atom-
transfer processes, site-selective activation originates at an
electron-rich, sterically accessible bond (Scheme 1A),[1b,d,3] or is
controlled kinetically by a directing group (Scheme 1B). A
hydroxyl group is attractive as a directing moiety because
alcohols are common within readily available small molecules.
To our knowledge, there are no general strategies for aliphatic γ-
C–H functionalization guided by a masked alcohol.[4,5] Herein
described are the first experiments to demonstrate that
sulfamate esters[6,7] can mediate 1,6-hydrogen-atom transfer
(HAT) processes to guide the light-promoted chlorination of
unactivated γ-C(sp3)–H centers.
β
H
δ
α
O
γ
ω
Me
N
O
N
hν
R
S
Me
ω
S
R
β
δ
α
γ
O
O
O O
PhH, 25 °C
Cl
1
2
Scheme 1. C(sp3)–H chlorination reactions
This approach is demonstrated in the course of site-selective
chlorine-transfer to convert N-chlorinated sulfamate esters 1 to
alkyl chlorides 2 (Scheme 1B). Predictable control has proven
more challenging in C(sp3)–H chlorination[21] than bromination
reactions,[12d,22,23] owing to the promiscuity of chlorine radical
promoted hydrogen-atom abstraction. Nevertheless, alkyl
chlorides are useful synthetic intermediates, and components of
bioactive small molecules, with >2000 known chlorine-containing
natural products.[24] Consequently, new technologies for
selective aliphatic C–H chlorination have potential to streamline
syntheses of bioactive small molecules.[25]
Our strategy for γ-functionalization is inspired by the modern
resurgence of interest[8,9] in the Hofmann-Löffler-Freytag
(HLF)[10–12] reaction. In traditional HLF processes, position
selectivity arises based on formation of an intermediate nitrogen-
centered radical that engages in a 1,5-HAT process[13] through a
kinetically favored, six-membered transition state. [14] By contrast,
we anticipate sulfamate esters may be capable of mediating 1,6-
HAT processes, which are rare[15] as they are expected to
proceed through seven-membered transition states, which are
often kinetically disfavored.[16] We hypothesize that sulfamate
esters enable 1,6-HAT because their elongated O–S and S–N
bonds (~1.58 Å) and compressed O–S–N bond angles
(~103°)[17] geometrically favor a seven-membered ring transition
state for C–H abstraction. The site-selectivity available through
these reactions complements that achieved using traditional
HLF chlorination transformations,[18] alternative guided
To minimize mechanistic uncertainty, we chose to generate
nitrogen-centered radicals by using light to homolyze nitrogen–
chlorine bonds of N-chlorosulfamate esters 1. N-chlorosulfamate
esters 1 are readily available from sulfamate esters 3[26] upon
treatment with trichloroisocyanuric acid or tert-butyl hypochlorite
(see supporting information for details). As anticipated,
photolysis of pentyl methylchlorosulfamate ester 1a results in
selective γ-chlorination at a methylene center (Table 1, entry 1,
C–H bond dissociation energy (BDE) ~ 98 kcal mol–1).[27] This
reaction does not occur in the absence of light, indicating that
photolysis initiates the reaction.
Chlorine-transfer proceeds from N-methyl-, N-tert-butyl-, N-
trifluoroethyl- and N-2-(pyridin-2-yl)isopropylchlorosulfamate
esters 1a–d (Table 1, entries 1–7). The corresponding series of
sulfamate esters 3 are predicted to differ in terms of N–H bond
acidity[28] by more than three pKa units, indicating that the
reaction tolerates broad electronic variations across N-alkyl
substituents. In all of these cases, the remaining mass balance
can be accounted for principally by reduced 3. Notably, in the
reaction of substrate 1b, <2% yield of δ-chlorinated product 4b
(not depicted) can be detected in the crude reaction mixture
along with desired γ-chlorinated 2b. While N-alkylsulfamate
esters facilitate chlorination, some N-arylsulfamate esters may
[a]
[+]
Melanie A. Short, J. Miles Blackburn, Prof. Dr. Jennifer L. Roizen
Duke University, Department of Chemistry, Box 90346, Durham,
North Carolina 27708–0354, USA
E-mail: j.roizen@duke.edu
These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.xxxx
This article is protected by copyright. All rights reserved.

10.1002/anie.201710322
Angewandte Chemie International Edition
COMMUNICATION
not engage in productive guided chlorine-transfer processes, as
photochemical irradiation of arylated 1e generates a complex
mixture of products.
with an electron withdrawing group, and engages in undirected
fluorination,[33] oxygenation,[34] amination,[35] azidation,[36] or
trifluoromethylthiolation[37] processes that functionalize C(7) in
preference to C(3). By contrast, the sulfamate ester-guided
chlorination installs chlorine at the electronically deactivated
C(3) position (entries 2–3).
Table 1. Chlorine-transfer robust to N-substitution
Cl
H
N
β
δ
ω
Me
α
O
γ
N
O
hν
R
S
Me
R
S
Table 2. Chlorine-transfer robust to O-alkyl substitution
O
O
PhH, 22 °C
O O
H
Cl
1
2
Cl
N
H
N
predictedb
β
substrate
for
δ
ω
α
O
γ
reaction
time
O
hν
pKa for
yield
(%)c
R
S
Me
R
S
Me
entrya
product (2)
R
H
N
O
O
PhH, 22 °C
O
O
chlorine-
transfer (1)
Cl
O
(min)
R
S
C5H11
1
2
O
O
3
time yield
(min) (%)b
entrya
substrate
product
12.65
12.74
45
15
60
15
60
90
85
98
83
96
86
70
Me
1a
1b
1b
1c
1c
1c
2a
2b
2b
2c
2c
2c
1
tBu
tBu
2d
3e
4
H
Cl
Me
Me
Me
Me
Cl
8
8
9.18
CH2CF3
CH2CF3
CH2CF3
H
F3C
N
O
1
F3C
N
O
1
5e
6f
2
5
2
5
S
S
91
15 2f,
1
O
O
O
O
N
H
R
H
Me
Me
1d
2d
7
11.05
45
66
Cl
H
N
Me
N
O
O
Me
1
1
tBu
R
S
R
S
2
3
15
15
85
96
2g,
2h,
generates complex mixture of products
O
O
O
O
3
3
CH2CF3
H
Cl
Cl
Me
H
Me
H
Me
Me
N
OC5H11
S
7
7
Me
Me
TBSO
O
O
F3C
1e
TBSO
H
H
Cl
N
H
N
4
5
F3C
O
F3C
F3C
O
54
15
2i,
2j,
[a] General reaction conditions: 1.0 equiv N-chlorosulfamate ester 1, PhH,
22 °C, irradiated with a blue Kessil lamp. [b] Aqueous ionization pKa values
have been predicted using SPARC.[28] [c] Isolated yield. [d] Trace amount of δ-
chlorinated product 4b (not depicted) detected in crude 1H NMR. See
Supporting Information for details. [e] Reaction run in PhCF3. [f] Reaction run
in PhCl.
S
S
S
O
O
O
O
H
Cl
Cl
N
NPhth
Me
NPhth
Me
H
N
F3C
O
O
240
82
87
S
H
Cl
O
O
O O
Me
Me
In these chlorine-transfer processes, site-selectivity is
orthogonal to that available through most atom-transfer
processes reliant on innate selectivity. In the productive
transformations of N-chlorinated 1a–d, chlorinated alkanes 2a–d
are formed with exquisite γ-selectivity, despite the fact that δ-
functionalization is expected to be favored under conditions that
rely on inherent selectivity (Table 1; Scheme 1A).
Cl
Me
H
H
N
Me
N
O
Me
O
Me
6
30
90
2k,
tBu
tBu
tBu
tBu
S
S
S
S
S
O
O
O
O
Cl
Cl
Cl
N
H
N
7
8
O
Ph
H
O
Ph
Cl
92
19
2l,
tBu
tBu
O
O
O
O
H
Cl
N
H
N
O
O
120
2m,
Guided selectivity is preserved across a range of O-alkyl
sulfamate esters (Table 2). For menthol-derived 1f, C(5)–H and
C(8)–H bonds are expected to have very similar electron
S
O
O
O O
Me
Me
Me
Me
densities.[29]
Nevertheless,
unguided
tertiary-selective
intermolecular oxidation[29] and amination[30] processes result in
selective functionalization of analogues at C(5), presumably
because the C(8)–H bond is sterically encumbered.[29] By
contrast, under the described conditions, chlorination occurs
exclusively at C(8)–H, which is poised to interact with the
sulfamate ester nitrogen-centered radical (entry 1) via a seven-
membered transition state. This position-selectivity is analogous
to that displayed in iron- and manganese-nitrene-mediated
Cl
N
9
15
36
2n,
H
N
F3C
O
O
F3C
O
H
Cl
S
S
O
O O
[a] General reaction conditions: 1.0 equiv N-chlorosulfamate ester 1, PhH,
22 °C, irradiated with a blue Kessil lamp. [b] Isolated yield.
Moreover, this guided functionalization process overcomes
selectivity that typically arises from differences in bond strength.
Pendant silyl ether 1i undergoes efficient and selective γ-
chlorination, without oxidation of the weak etherial C–H bonds
(BDE ~ 85 kcal mol–1, entry 4).[27]
intramolecular amination reactions of sulfamate esters.[31,32
]
Furthermore, the directed chlorination reaction overcomes
the innate site-selectivity that arises from inductive deactivation
in unguided oxidation processes. In unguided C–H
functionalization reactions, proximity to inductively electron-
withdrawing groups deactivates C–H bonds to oxidation. This
phenomenon is evident when 3,7-dimethyloctanol is masked
In addition to differentially masked diols, the reaction
conditions are compatible with a variety of functional groups.
Sulfamate esters derived from N-protected amino alcohols
engage in selective atom-transfer, as phthalimidyl 1j provides
chlorinated 2j in 82% isolated yield (entry 5). As noted
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10.1002/anie.201710322
Angewandte Chemie International Edition
COMMUNICATION
previously, the reaction also allows pendant heteroaromatic
moieties (Table 1, entry 7) and fluorides (Table 1, entries 4–6;
Table 2, entries 1, 3–5, 9).
molecule per absorbed photon (Φ ≤ 1), a radical chain
propagation mechanism could provide multiple equivalents of
the product per absorbed photon (Φ > 1).
This method transforms C(sp3)–H bonds at secondary,
tertiary (BDE ~ 96 kcal mol–1),[27] and benzylic centers (BDE ~ 90
kcal mol–1)[27] in synthetically useful yields (entries 1–8).
Generally, chlorination of γ-C(sp3)–H centers occurs in
preference to β-C–H centers, even when the γ-C–H bond is
primary and significantly stronger (BDE ~ 101 kcal mol–1)[27] than
a secondary β-C–H bond. For example, chlorination of propyl
tert-butylsulfamate ester 1m and (–)-borneol derivative 1n occur
at the stronger primary C–H bonds, albeit with diminished
efficiency (entries 8–9). While each of these substrates displays
a geometrically accessible β-methylene center, chlorination at
these positions is not detected. Instead, dehalogenated
sulfamate esters 3m and 3n are the primary byproducts of these
transformations. An analogous reactivity trend has been
documented with White’s manganese-catalyzed intramolecular
amination with sulfamate esters.[32]
Quantum yield measurements have been performed to
provide insight into the operative reaction mechanism,[38] and
provide evidence that the reaction proceeds through a light-
initiated chain propagation mechanism. Briefly, standard
chemical actinometry using potassium ferrioxalate allowed us to
determine the photon flux of a fluorimeter at 313 nm.[38,39] After
15 minutes of irradiation of N-chlorinated 1b in benzene at 313
nm in the calibrated fluorimeter, 68% conversion to chloroalkane
2b is observed. This yield corresponds to 77 equivalents of
product formed per absorbed photon (Φ = 77), indicating that
this reaction proceeds through a chain propagation mechanism.
This sulfamate ester-guided HLF reaction is expected to
provide a powerful and general platform to complement current
HLF technologies. This research is among the first to establish
that sulfamate esters can mediate 1,6-HAT such that the
generated carbon-centered radicals can be trapped efficiently in
guided intermolecular reactions. Furthermore, the method
provides efficient access to secondary and tertiary alkyl
chlorides, a valuable class of synthetic intermediates, with novel
and predictable site-selectivity.
In principle, this chlorination reaction could proceed through
a closed cycle and/or a radical chain propagation mechanism
(Scheme 2). In either pathway, initiation would occur by light-
promoted N–Cl bond homolysis, thereby converting N-
chlorosulfamate ester 1b to chlorine radical and sulfamyl radical
5b. The resulting nitrogen-centered radical 5b mediates an
intramolecular 1,6-HAT to generate a carbon-centered radical
6b with exquisite position selectivity. Subsequent divergence in
carbon–chlorine bond forming events then distinguishes
between the proposed pathways. In the closed radical cycle
Acknowledgements
This project was funded by the American Chemical Society
Petroleum Research Fund Doctoral New Investigator Program
(PRF# 54824-DNI1) and by Duke University. JMB was
supported by the National Institute of General Medical Sciences
(T32GM007105-41) and the Burroughs Wellcome Fellowship.
MAS was supported by a NSF predoctoral fellowship (NSF DGF
1106401). HRMS data were obtained by George Dubay and
Matias Horst of Duke University. Characterization data were
obtained on instrumentation secured by funding from the NSF
(CHE-0923097, ESI-MS, George Dubay, Duke Dept. of
Chemistry Instrument Center), or the NSF, the NIH, HHMI, the
North Carolina Biotechnology Center and Duke (Duke Magnetic
Resonance Spectroscopy Center). We thank J. Du Bois, N.
Burns, and R. Zare (Stanford University) for sharing results prior
to publication.
mechanism,
intermediate
carbon-centered
radical
6b
recombines with the chlorine radical to terminate the reaction
and provide 2b (not depicted). Alternatively, carbon-centered
radical 6b could engage in chlorine-atom abstraction with
another equivalent of N-chlorosulfamate ester 1b (Scheme 2).
This sequence would release desired halogenated 2b, along
with another equivalent of radicalloid 5b, which could propagate
this chain reaction.
H
N
Cl
N
hν
(313 nm)
O
O
tBu
tBu
Me
S
Me
S
PhH
O
O
O O
H
Cl
1b
2b
initiation
chlorine-atom
transfer
Cl
H
N
O
HAT
N
O
tBu
Keywords: radical reactions • hydrogen transfer • halogenation
S
Me
tBu
S
Me
O
O
H
5b
O
O
6b
• directing group • chlorination
Cl
N
propagation
+
O
chlorine-atom
transfer
tBu
[1]
For select reviews, see: a) R. G. Bergman, Nature 2007, 446, 391; b) H.
M. L. Davies, J. R. Manning, Nature 2008, 451, 417; c) T. W. Lyons, M.
S. Sanford, Chem. Rev. 2010, 110, 1147; d) M. C. White, Science
2012, 335, 807; e) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu,
Chem. Rev. 2017, 117, 8754.
Me
S
O
O
H
1b
68% yield, 15 min
quantum yield (Φ) = (2b formed / photon absorbed) = 77
Scheme 2. Chlorination proceeds through light-initiated chain-propagation
[2]
[3]
For a review, see: J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew.
Chem. Int. Ed. 2012, 51, 8960; Angew. Chem. 2012, 124, 9092.
For select resources, see: a) K. Chen, A. Eschenmoser, P. S. Baran,
Angew. Chem. Int. Ed. 2009, 48, 9705; Angew. Chem. 2009, 121,
9885; b) T. Brückl, R. D. Baxter, Y. Ishihara, P. S. Baran, Acc. Chem.
Res. 2012, 45, 826–839; c) T. Cernak, K. D. Dykstra, S. Tyagarajan, P.
Vachal, S. W. Krska, Chem. Soc. Rev. 2016, 45, 546.
These mechanistic hypotheses differ in terms of the number
of product equivalents that can be generated per absorbed
photon, a relationship that defines quantum yield (Φ). While a
closed radical cycle could furnish a maximum of one product
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10.1002/anie.201710322
Angewandte Chemie International Edition
COMMUNICATION
[4]
[5]
F. Mo, J. R. Tabor, G. Dong, Chem. Lett. 2014, 43, 264.
For alcohol-guided γ-C(sp3)–H oxygenation, see: a) E. M. Simmons, J.
F. Hartwig, Nature 2012, 483, 70. For carbamate-guided oxidation that
is selective for oxidation of benzylic or tertiary β-C(sp3)–H or γ-C(sp3)–H
centers, see b) K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem. Soc.
2008, 130, 7247.
d) N. C. Deno, R. Fishbein, J. C. Wyckoff, J. Am. Chem. Soc. 1971, 93,
2065.
[19]
a) R. Breslow, R. J. Corcoran, B. B. Snider, R. J. Doll, P. L. Khanna, R.
Kaleya, J. Am. Chem. Soc. 1977, 99, 905; b) R. Breslow, D. Heyer, J.
Am. Chem. Soc. 1982, 104, 2045.
[20] For a visible light-promoted C(sp3)–H chlorination reaction, see: a) R. A.
Quinn, Z. A. Könst, S. E. Michalak, Y. Schmidt, A. R. Szklarski, A. R.
Flores, S. Nam, D. A. Horne, C. D. Vanderwal, E. Alexanian, J. Am.
Chem. Soc. 2016, 138, 696; For select manganese-catalyzed C(sp3)–H
chlorination reactions, see: b) W. Liu, J. T. Groves, J. Am. Chem. Soc.
2010, 132, 12847; c) W. Liu, J. T. Groves, Acc. Chem. Res. 2015, 48,
1727.
[6]
[7]
D. N. Zalatan, Du Bois, J., Synlett 2009, 143.
a) J. V. Ruppel, R. M. Kamble, X. P. Zhang, Org. Lett. 2007, 9, 4889; b)
H. Lu, K. Lang, H. Jiang, L. Wojtas, X. P. Zhang, Chem. Sci. 2016, 7,
6934.
[8]
[9]
a) S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603; b) T. Xiong, Q. Zhang,
Chem. Soc. Rev. 2016, 45, 3069. c) M. D. Kärkäs, ACS Catal. 2017, 7,
4999.
[21] P. S. Skell, H. N. Baxter, J. Am. Chem. Soc. 1985, 107, 2823.
[22] C. Djerassi, Chem. Rev. 1948, 43, 271.
For select examples, see: a) G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu,
R. R. Knowles, Nature 2016, 539, 268; b) J. C. K. Chu, T. Rovis, Nature
2016, 539, 272. c) W. Shu, C. Nevado, Angew. Chem. Int. Ed. 2017, 56,
1881. d) E. A. Wappes, K. M. Nakafuka, D. A. Nagib, J. Am. Chem. Soc.
2017, 139, 10204. e) D.-F. Chen, J. C. K. Chu, T. Rovis, J. Am. Chem.
Soc. 2017, 139, 14897.
[23] For select recent advances in guided alkane bromination, see: a) T. Liu,
M. C. Myers, J.-Q. Yu, Angew. Chem. Int. Ed. 2017, 56, 306; Angew.
Chem. 2017, 129, 312; b) R.-Y. Zhu, T. G. Saint-Denis, Y. Shao, J. He,
J. D. Sieber, C. H. Senanayake, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139,
5724.
[10] M. E. Wolff, Chem. Rev. 1963, 63, 55.
[24] Gribble, G. W. Naturally Occurring Organohalogen Compounds: A
Comprehensive Update; Springer-Verlag: Weinheim, Germany, 2010.
[25] W. R. Gutenkunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976.
[26] J. M. Blackburn, M. A. Short, T. Castanheiro, S. K. Ayer, T. D. Muellers,
J. L. Roizen, Org. Lett. 2017, 19, doi: 10.1021/acs.orglett.7b03059.
[27] John R. Rumble, Ed., CRC Handbook of Chemistry and Physics 98th
Edition (Internet Version 2018) CRC Press/Taylor & Francis, Boca
Raton, FL.
[11] a) A. W. Hofmann, Chem. Ber. 1883, 16, 558; b) K. Löffler, C. Freytag,
Chem. Ber. 1909, 42, 3427.
[12] For select tactical advances, see: a) P. De Armas, R. Carrau, J. I.
Concepción, C. G. Francisco, R. Hernández, E. Suárez, Tetrahedron
Lett. 1985, 26, 2493; b) C. Martínez, K. Muñiz, Angew. Chem. Int. Ed.
2015, 54, 8287; Angew. Chem. 2015, 127, 8405; c) N. R. Paz, D.
Rodríguez-Sosa, H. Valdéz, R. Marticorena, D. Melián, M. B. Copano,
C. C. González, A. J. Herrera, Org. Lett. 2015, 17, 2370; d) E. A.
Wappes, S. C. Fosu, T. C. Chopko, D. A. Nagib, Angew. Chem. Int. Ed.
2016, 55, 9974; Angew. Chem. 2016, 128, 10128.
[28] a) S. H. Hilal, S. W. Karickhoff, Quant. Struct.-Act. Relat. 1995, 14, 348;
b) http://www.archemcalc.com/sparc.html.
See
the
Supporting
Information for additional details on how calculations were performed.
[29] M. S. Chen, M. C. White, Science 2007, 318, 783.
[30] J. L. Roizen, D. N. Zalatan, J. Du Bois, Angew. Chem. Int. Ed. 2013, 52,
11343; Angew. Chem. 2013, 52, 11553.
[13] For select recent reviews focusing on intramolecular 1,5-HAT, see: a) J.
Robertson, J. Pillai, R. K. Lush, Chem. Soc. Rev. 2001, 30, 94; b) Ž.
Čeković, J. Serb. Chem. Soc. 2005, 70, 287; c) S. Chiba, H. Chen. Org.
Biomol. Chem. 2014, 12, 4051.
[31] Y. Liu, X. Guan, E. Lai-Ming Wong, P. Liu, J.-S. Huang, C.-M. Che, J.
Am. Chem. Soc. 2013, 135, 7194.
[14] a) K. Löffler, Ber. 1910, 43, 2035. b) E. J. Corey, W. R. Hertler, J. Org.
Chem. 1960, 82, 1657; c) B. F. Yates, L. Radom, J. Am. Chem. Soc.
1987, 109, 2910. d) I. Janovsky, W. Knolle, S. Naumov, F. Williams,
Chem. Eur. J. 2004, 10, 5524.
[32] S. M. Paradine, J. R. Griffin, J. Zhao, A. L. Petronico, S. M. Miller, M. C.
White, Nature Chem. 2015, 7, 987.
[33] a) C. Gal, G. Ben-Shoshan, S. Rozen, Tetrahedron Lett. 1980, 21,
5067; b) S. Rozen, C. Gal, J. Org. Chem. 1987, 52, 4928.
[34] For a pioneering example, see: B. H. Brodsky, J. Du Bois, J. Am. Chem.
Soc. 2005, 127, 15391.
[15] M. Nechab, S. Mondal, M. P. Bertrand, Chem. Eur. J. 2014, 20, 16034.
[16] a) A. E. Dorigo, K. N. Houk, J. Am. Chem. Soc. 1987, 109, 2195. b) A.
E. Dorigo, K. N. Houk, J. Org. Chem. 1988, 53, 1650. c) A. E. Dorigo, M.
A. McCarrick, R. J. Loncharich, K. N. Houk, J. Am. Chem. Soc. 1989,
112, 7508.
[35] For a pioneering example, see: F. Collet, C. Lescot, C. Liang, P.
Dauban, Dalton Trans. 2010, 39, 10401.
[17] C. G. Espino, P. M. Wehn, J. Chow, J. Du Bois, J. Am. Chem. Soc.
2001, 123, 6935.
[18] For select recent visible light-promoted C(sp3)–H chlorination reactions,
see: a) Q. Qin, S. Yu, Org. Lett. 2015, 17, 1894; b) J. Ozawa, M. Kanai,
Org. Lett. 2017, 19, 1430. For select historic advances, see: c) F.
Minisci, R. Galli, A. Galli, R. Bernardi, Tetrahedron Lett. 1967, 8, 2207;
[36] A. Sharma, J. F. Hartwig, Nature 2015, 517, 600.
[37] S. Mukherjee, B. Maji, A. Tlahuext-Aca, F. Glorius, J. Am. Chem. Soc.
2016, 138, 16200.
[38] M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6, 5426.
[39] C. G. Hatchard, C. A. Parker, Proc. R. Soc. Lond. A 1956, 235, 518.
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10.1002/anie.201710322
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Melanie A. Short, J. Miles Blackburn,
Jennifer L. Roizen*
light
H
N
Cl
N
O
O
R1
S
Me
R1
S
Me
• sulfamate ester directing group
• γ-selective C(sp3)–H chlorination
• 1º, 2º, and 3º C–H bonds
O
O
O
O
Cl
Page No. – Page No.
H
Sulfamate Esters Guide Radical-
Mediated Chlorination of Aliphatic
C-H Bonds
Guided Chlorination: Aliphatic γ-C(sp3)–H chlorination is directed by a sulfamate-
ester masked alcohol. This reaction involves a light-initiated N–Cl bond homolysis,
followed by an unusual radical-mediated 1,6-hydrogen-atom abstraction with
subsequent chlorination enabled by a chain-propagation process. Through this
process, chlorine atoms can be selectively installed at primary, secondary, and
tertiary centers with predictable selectivity.
This article is protected by copyright. All rights reserved.