Development of an Imine Chaperone for Selective C-H Functionalization of Alcohols via Radical Relay

Article abstract of DOI:10.1021/acs.joc.9b02052

The design of a radical relay chaperone to promote selective C-H functionalizations is described. A saccharin-based imine was found to be uniquely suited to effect C-H amination of alcohols via an in situ generated hemiaminal. This radical chaperone facilitates the mild generation of an N-centered radical while also directing its regioselective H atom transfer (HAT) to the β carbon of an alcohol. Upon β C-H halogenation, aminocyclization, and reductive cleavage, an NH₂ is formally added vicinal to an alcohol. The development, synthetic utility, and chemo-, regio-, and stereoselectivity of this imine chaperone-mediated C-H amination is presented herein.

Full text of DOI:10.1021/acs.joc.9b02052

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Development of an Imine Chaperone for Selective C−H
Functionalization of Alcohols via Radical Relay
Kohki M. Nakafuku,† Raymond K. Twumasi,† Avassaya Vanitcha,† Ethan A. Wappes,
Kayambu Namitharan, Mathieu Bekkaye, and David A. Nagib*
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
S
* Supporting Information
ABSTRACT: The design of a radical relay chaperone to promote
selective C−H functionalizations is described. A saccharin-based imine
was found to be uniquely suited to effect C−H amination of alcohols
via an in situ generated hemiaminal. This radical chaperone facilitates
the mild generation of an N-centered radical while also directing its
regioselective H atom transfer (HAT) to the β carbon of an alcohol.
Upon β C−H halogenation, aminocyclization, and reductive cleavage,
an NH2 is formally added vicinal to an alcohol. The development, synthetic utility, and chemo-, regio-, and stereoselectivity of
this imine chaperone-mediated C−H amination is presented herein.
INTRODUCTION
■
Alcohols, ubiquitous motifs in synthesis, are ideal recognition
elements for directing C−H functionalization within complex
molecules.1 In the metal-mediated realm, alcohols have been
converted to carbamates, silyl ethers, and oximes, which serve
as directing groups to facilitate Pd, Ru, or Ir coordination and
C−H functionalization via a metallocycle.2,3 In the radical-
mediated arena, pioneering efforts by Barton, Smith, Walling,
̌
́
and Cekovic demonstrated the utility of O-centered radicals to
effect regioselective C−H functionalization via 1,5-intra-
molecular H atom transfer (HAT).4−6 Complementarily,
Breslow recognized the opportunity to append radical
precursors, or chaperones, onto alcohols and demonstrated
that remarkably selective, remote C−H halogenations and
oxidations were possible.7 In recent years, the laboratories of
Baran, Gevorgyan, Kanai, Roizen, Chen, Kumar, and ours have
made contributions toward the development of additional
radical precursors that may be appended to alcohols to
facilitate HAT.8,9 Over the course of our own studies in this
arena,9 we wondered if a radical relay chaperone could
catalytically (i) dock onto an alcohol, (ii) mediate HAT, and
(iii) be released to engage another alcoholin an enzyme-like
fashion. Inspired by the transient hemiaminals independently
developed by Tan and Beauchemin to promote regioselective
functionalization of allyl alcohols and amines10 as well as
complementary C−H functionalization strategies by others,11
we proposed an imine catalyst might serve this role and
facilitate selective HAT.
Figure 1. Design of an imine radical relay chaperone strategy for β
C−H functionalization of alcohols via transient hemiaminals.
provide a β substituted alcohol product, along with the
regenerated imine catalyst A.
RESULTS AND DISCUSSION
■
To investigate our proposed strategy, a series of imines were
designed, synthesized, and stoichiometrically evaluated in each
of the proposed, elementary steps: (i) hemiaminal formation,
(ii) C−H functionalization, (iii) and imine release (Figure 2).
On the basis of our previous successful efforts effecting
intramolecular HAT from Ts amides,12 our initial imine design
included Ts substituents (Figure 2b, I−V). Upon evaluation of
Our design, shown in Figure 1, entails the addition of an
alcohol to imine catalyst A to generate transient hemiaminal B.
We envisioned the exposed sp3 N of B may then be
chemoselectively oxidized to generate N-centered radical C,
which should undergo regioselective 1,5-HAT4 to afford β C-
centered radical D. Upon combination with a radical trap, the
β C−H functionalized hemiaminal E may then collapse to
Special Issue: C-H Bond Functionalization
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b02052
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The Journal of Organic Chemistry
Article
Figure 2. Development of an imine radical relay chaperone for β C−H functionalization of alcohols.
aldehyde-derived Ts imines (I), we were pleased to find that
they are readily converted to hemiaminals. However, these
intermediates are highly prone to undergo β scission, rather
than 1,5-HAT (Figure 2c).
and nonenolizable (Figure 2d). As we brainstormed a molecule
to meet these criteria, it occurred to us that an endocyclic Ts-
imine may serve this purpose. To this end, we sought to use
saccharin-type imine 3.13 The imine was readily prepared in a
two-step synthesis from TsNH-tBu 1. The first step entails a
sulfonamide-directed ortho-lithiation, followed by quenching
with ethyl trifluoroacetate to afford ketone 2 in 63% yield.14
Upon treatment with TFA at 135 °C for 12 h, this ketone was
then cyclized, deprotected, and dehydrated in a single step to
afford imine chaperone 3 as a crystalline, white solid in 95%
yield. To our delight, alcohols readily add to this imine in
MeCN at room temperature. Moreover, when subjected to NaI
and PhI(OAc)2,12 the resulting hemiaminal 4 undergoes
selective HAT to afford β C−H halide 5 (X = I), which is
unstable and not isolated. To our surprise, however, when
attempting to release the chaperone by treatment with base
(K2HPO4), an intramolecular displacement instead occurs to
afford aminated adduct 6. Although net incorporation of the
chaperone into the product via a covalent C−N bond prevents
its use as a catalyst, the ongoing challenge and synthetic utility
of C−H amination led us to continue developing this
reaction.15 Notably, when K2HPO4 is included in the direct
C−H functionalization of 4, the entire cascade directly results
in efficient formation of the C−H aminated oxazolidine 6
(79% yield). Interestingly, along with exceptional regioselec-
Interestingly, hemiaminals from each of the aldehydes that
i
t
were prepared (I; R = Me, Et, Pr, Bu) resulted mainly in the
formation of imidate side productseven in cases that would
formally furnish Me or Et radicals. We next turned to ketone
derived imines (II−V) with the hopes of blocking the
oxidizable carbon. Unfortunately, our attempts to convert
these ketimines II to hemiaminals were unfruitful, likely due to
attenuated electrophilicity. As a possible solution, we next
incorporated a withdrawing ester substituent. However, α-
imino ester III readily undergoes transesterification rather than
hemiaminal formation. As our next design, we instead
incorporated a withdrawing amide to prevent competitive
attack of the imine at the adjacent carbonyl. However,
hemiaminals of cyclic amide IV, derived from isatin, were
highly prone to hydrolysis. Finally, we investigated ninhydrin-
based imine V, bearing an imine with two flanking ketones.
However, while V readily affords hemiaminals, these
intermediates undergo undesired rearrangements.
In summarizing the necessary design elements of a suitable
HAT chaperone from these studies, we proposed the imine
should be ketone-derived, cyclic, substituted with an EWG,
B
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tivity (>20:1 β), this rigid, polycyclic heterocycle is accessed as
a single diastereomer (>20:1) via net, cis C−H amination.
We next turned to developing a one-pot protocol for directly
converting alcohols to their β C−H aminated analogues (Table
1). After stirring octanol (0.1 mmol) and imine 3 (2 equiv) in
Table 1. Development of a One-Pot β C−H Amination of
Alcohols
entry
oxidant
base
product 6
1
2
3
4
5
6
7
8
NaI, PhI(OAc)2
NaI, PhI(OAc)2
I2, PhI(OAc)2
I2, PhI(OAc)2
NIS
NIS
NBS
NBS
−
+
−
+
−
+
−
+
19% 5 (X = I)
52%, >20:1 dr
13% 5 (X = I)
41%, >20:1 dr
39%, >20:1 dr
62%, >20:1 dr
42%, >20:1 dr
72% (67%), >20:1 dr
MeCN (0.2 M) at 23 °C for 2 h, hemiaminal 4 was formed
1
quantitatively, as determined by crude H NMR. Oxidant and
K2HPO4 were then added, and the reaction was stirred under
visible light irradiation (90 W blue LED) at 23 °C until
complete consumption of the in situ generated hemiaminal
(2−24 h). As illustrated in Table 1, this one-pot procedure for
direct alcohol C−H functionalization either affords β iodide 5
(19% by NMR; without base), or oxazolidine 6 is formed in a
slightly lower yield (52%, >20:1 dr; with base) than the
stepwise procedure (entries 1 and 2). To improve this one-pot
́
protocol, we also explored the Suarez method (I2, PhI-
(OAc)2)16 for amidyl radical HAT. However, these conditions
resulted in slightly diminished yields. On the other hand,
employing N-halo succinimides as the oxidant afforded
improved yields with either NIS (entries 5 and 6, up to 62%
yield) or NBS (entries 7 and 8, up to 72% yield). Interestingly,
although base is not necessary to promote cyclization with
these reagents, its incorporation improves overall efficiency
(entry 8, 67% isolated yield). To our delight, each of these C−
H aminations of octanol are both exquisitely diastereoselective
(>20:1 syn) and regioselective (>20:1 β).
Synthetic Scope. In order to determine the synthetic
utility of this new, imine-chaperone-mediated β C−H
amination, we subjected a series of alcohols to this one-pot
protocol. As shown in Figure 3, a wide range of alcohols
undergo the radical relay mechanism to afford regioselective
C−H amination (>20:1 β in all cases). For example, propanol,
4-tBu-cyclohexanol, and phenethyl alcohol each afford
oxazolidine efficiently (7−9; 62−75% yield) and in high
diastereoselectivity (>20:1). With the hopes of probing the
synthetic utility of this HAT-mediated amination, we then
investigated a range of stereoelectronically diverse 2-
arylethanols. To our delight, ortho (10 and 11), meta (12
and 13), and para (14−17) substitution are all well-tolerated,
including both electronically rich and deficient substituents
(OMe, Me, Cl, F, CF3). Notably, incorporation of a 2-pyridyl
ethanol (18) also illustrates the applicability of this β C−H
amination to alcohols with medicinal relevance. To this end,
we also noted that β amino alcohol 16 is an interesting
Figure 3. Synthetic evaluation of the imine chaperone strategy for β
C−H amination of alcohols.
isomeric analogue of the neurotransmitter, octopamine,
wherein the N and O of the β amino alcohol are inverted.
Regioselectivity Investigation. Motivated by the com-
plete regioselectivity observed in all cases but especially for 1-
octanol, we sought to design and explore a series of
regioselectivity probes to interrogate the HAT selectivity. To
this end, we synthesized alcohols containing weaker C−H
bonds at the γ positions, with the intention to quantify the
tendency for 1,5-HAT versus the next most likely 1,6-HAT
mechanism. In the case of a slightly weaker tertiary C−H
(BDE: 96 kcal/mol vs secondary C−H, 98 kcal/mol),17 a 3:1
regiomeric ratio (rr) was observed favoring the 1,5-HAT-
mediated β amine (19). However, when an even weaker α-keto
C−H was used (BDE: 94 kcal/mol), complete β selectivity was
instead observed (20, >20:1 rr), indicating that C−H polarity
also plays an important role. Finally, when a much weaker
benzylic C−H is incorporated (BDE: 90 kcal/mol), we
observed a switch in regioselectivity to afford γ amine 21
instead (3:1 rr)illustrating that 1,6-HAT may compete
under strongly biased environments.
C
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or KMnO4 stain. All yields are averages of at least two experimental
runs. All regioselectivity (rr) and diastereoselectivity (dr) values are
Stereoselectivity Investigation. In addition to regiose-
lectivity, we were also interested in investigating the
diastereoselectivity of this HAT mechanism, especially for
secondary alcohols (Figure 4). In this vein, we subjected both
1
measured by H NMR analysis of crude reaction materials.
Nuclear magnetic resonance (NMR) spectra (1H, 13C) were
recorded using either a Bruker AVIII 400 or AVIII 600 MHz NMR
1
spectrometer. H and 13C NMR chemical shifts are reported in parts
per million and referenced to residual CHCl3 signals in CDCl3 (1H, δ
1
7.26; 13C, δ 77.16). H NMR data are reported as follows: chemical
shifts (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, b = broad, ap = apparent), coupling constant
(Hz), relative integral. Data for 13C are reported in terms of chemical
shift and multiplicity where appropriate. High-resolution mass
spectrometry (HRMS) data were obtained using a Bruker MicrOTOF
(ESI). Measured values are reported to four decimal places and are
within 5 ppm of the calculated value, which are based on the most
abundant isotope. Infrared (IR) spectra were recorded using a
Thermo Fisher Nicolet iS10 FT-IR and are reported in terms of
frequency of absorption (cm−1). Melting points were determined
using an Electrotherman IA9000.
Figure 4. Diastereoselectivity probe.
conformationally locked isomers of 4-tBu-cyclohexanol, cis-22
and trans-22, to the β C−H amination protocol. Surprisingly,
whereas cis-22 efficiently provides oxazolidine 8, trans-22 does
not afford any C−H functionalized product. Since vicinal H
atoms are available for abstraction by either isomer, we
interpret this divergent reactivity as evidence of a preference
for amination by the axial oxygen-bound chaperone over the
equatorial one.
Additionally, the cis stereochemical arrangement of the
nitrogen and oxygen substituents on the central oxazolidine is
supported by X-ray crystallography data (see the Supporting
Information for full details). Lastly, as shown in Figure 5, the
imine chaperone may be removed by reduction with SmI2.
Acidic hydrolysis with TfOH furnishes the free β amino
alcohol (50% yield).
Photochemical reactions were performed by placing a 90 W Kessil
blue LED lamp (λmax = 459 nm) approximately 5 cm from the
reaction vessel (borosilicate glass, without an added filter), along with
a fan behind the reaction vessel.
Synthesis of Imine Chaperone (3). N-(tert-Butyl)-4-methyl-
benzenesulfonamide (1). To a stirred suspension of tertbutylamine
(27.3 mL, 260 mmol, 2.0 equiv) and distilled triethylamine (54.4 mL,
390 mmol, 3.0 equiv) in dry CH2Cl2 (100 mL) at 0 °C was added 4-
toluenesulfonyl chloride (24.8 g, 130 mmol, 1.0 equiv) portion-wise at
0 °C. After complete addition, the resulting suspension was warmed
to room temperature and stirred for 12 h. The mixture was quenched
with a 3 M HCl aqueous solution (100 mL) at 0 °C. The aqueous
layer was extracted with CH2Cl2 (3 × 100 mL). Combined organic
extracts were washed with brine (1 × 100 mL), dried over MgSO4,
and filtered. The combined organic layer was concentrated under
reduced pressure to afford the title compound as a white solid (28.1 g,
95% yield), which was used without further purification. TLC: Rf =
0.21 in 20% EtOAc/hexanes; MP: 110.5−112.0 °C; IR (neat) ν
1
(cm−1): 3259, 2987, 2972, 1597, 1475, 1299, 1181, 1109, 995; H
NMR (CDCl3, 400 MHz) δ (ppm): 7.78 (d, J = 8.3 Hz, 2H), 7.27 (d,
J = 8.1 Hz, 2H), 4.76 (br s, 1H), 2.41 (s, 3H), 1.21 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ (ppm): 142.9, 140.7, 129.6, 127.1, 54.7, 30.3,
21.6; HRMS (m/z ESI-TOF): calculated for C9H6F3NO2SH+ [M +
H]+ 250.0150, found 250.0141.
N-(tert-Butyl)-4-methyl-2-(2, 2, 2-trifluoroacetyl)-
benzenesulfonamide (2). To a stirring solution of 1 (6.0 g, 26.4
mmol, 1.0 equiv) and distilled TMEDA (11.8 mL, 79.1 mmol, 3.0
Figure 5. Removal of chaperone.
n
equiv) at 0 °C was added a solution of BuLi (28.7 mL, 2.3 M in
In summary, we have developed an imine chaperone, which
is capable of transforming alcohols into β amino alcohols by a
chemo-, regio-, and stereoselective HAT mechanism. We have
interrogated the viability of various chaperone scaffolds in
promoting this HAT, in addition to probing the synthetic
utility and selectivity parameters of a saccharin-based imine.
We expect the design principles observed for the discovery of
this radical chaperone will allow the development of more C−
H functionalization technologies using this strategy.
hexanes, 66.0 mmol, 2.5 equiv) dropwise over 5 min. After complete
addition, the resulting suspension was stirred at 0 °C for 30 min. The
reaction mixture was cooled to −78 °C. A solution of ethyl 2,2,2-
trifluoroacetate (9.4 mL, 79.1 mmol, 3 equiv) was added dropwise
over 10 min. The resulting solution was then stirred for 3 h, while
slowly warming to room temperature. The mixture was cooled to 0 °C
and quenched with a 3 M HCl aqueous solution (100 mL). The
aqueous layer was extracted with Et2O three times (3 × 50 mL).
Combined organic extracts were washed with brine (1 × 100 mL),
dried over MgSO4, and filtered. The combined organic layer was
concentrated under reduced pressure to afford a crude residue, which
was purified on silica gel using hexanes/Et2O as eluent (gradient from
100/0 to 30/70) to afford the title compound as a yellow oil (5.38g,
63% yield), which becomes a white solid. TLC: Rf = 0.21 in 20%
EtOAc/hexanes; IR (neat) ν (cm−1): 3268, 2977, 1748, 1597, 1423,
1316, 1171, 1136, 1073, 970; 1H NMR (CDCl3, 400 MHz) δ (ppm):
7.98 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 4.88
(br s, 1H), 2.49 (s, 3H), 1.24 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ (ppm): 186.1 (q, J2CF = 37.4 Hz), 143.3, 140.5, 133.2, 131.5, 129.7,
128.5 (q, J3CF = 2.0 Hz), 115.8 (q, J1CF = 291.2 Hz), 55.5, 30.2, 21.5;
19F NMR (CDCl3, 376 MHz) δ (ppm): −73.8; HRMS (m/z ESI-
TOF): calculated for C13H16F3NO3SNa+ [M + Na]+ 346.0695, found
346.0705. Data in accordance with those reported in the literature.13
EXPERIMENTAL SECTION
■
Materials and Methods. All reagents, unless otherwise stated,
were used as supplied from commercial sources without further
purification. NBS, K2HPO4, and other solid reagents were dried under
a vacuum before use. Solvents were purified in the following manner.
Acetonitrile (MeCN) was distilled over calcium hydride. CH2Cl2,
THF, Et2O, and DMF were degassed with N2 and dried by passing
through columns containing alumina, copper, or molecular sieves.
Flash column chromatography, or preparative thin-layer chromatog-
raphy, was performed with Silicycle F60 (230−400 mesh) silica gel.
Thin layer chromatography (TLC) analyses were performed using
EMD 60 F254 TLC plates and visualized by fluorescence quenching
D
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5-Methyl-3-(trifluoromethyl)benzo[d]isothiazole 1,1-Dioxide (3).
To a solution of 2 (2.0 g, 6.2 mmol, 1.0 equiv) in degassed toluene (2
mL) in a pressure tube, trifluoromethyl acetic acid (2.4 mL, 31.0
mmol, 5.0 equiv) was added under a flow of dry nitrogen. The
reaction mixture was stirred for 12 h at 135 °C. Then, toluene and
acid were removed via azeotrope with dry CH2Cl2 (2 × 10 mL) under
vacuo. The title compound was isolated as an oil, which solidified
upon further drying (light brown solid, 1.5 g, 95% yield). Due to its
hydrophilicity, this crude imine was used directly in the following
reactions. MP: 127.1−128.9 °C; TLC: Rf = 0.26 in 40% EtOAc/
hexanes; IR (neat) ν (cm−1): 3356, 3250, 2981, 2361, 2341, 1601,
1286, 1174, 1053; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.88 (d, J =
7.8 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.26 (s, 1H), 2.56 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ (ppm): 160.7 (q, J2CF = 40.0 Hz), 146.5,
138.0, 135.8, 133.7, 126.1, 123.5, 118.9 (q, J1CF = 278.4 Hz), 22.0; 19F
NMR (CDCl3, 376 MHz) δ (ppm): −67.7; HRMS (m/z ESI-TOF):
calculated for C9H6F3NO2SH+ [M + H]+ 250.0105, found 250.0141.
General Procedure for One-Pot β C−H Amination of
Primary Alcohols (GP1). To a stirred solution of 3 (49.8 mg, 0.2
mmol, 2.0 equiv) in an oven-dried septa vial, the appropriate alcohol
(0.1 mmol, 1.0 equiv) in acetonitrile (0.5 mL, 0.2 M) was added. The
reaction was stirred at room temperature (23 °C) for 2 h. The solvent
was removed, and the mixture was dried under a vacuum. In a
glovebox, recrystallized NBS (71.2 mg, 0.4 mmol, 4.0 equiv) and
oven-dried K2HPO4 (78.4 mg, 0.45 mmol, 4.5 equiv) were added to
the reaction vial. Freshly distilled and degassed acetonitrile (3 mL)
was then added to the vial. The reaction was irradiated with a blue 90
W LED for 24 h while being cooled with a fan to keep the
temperature constant (vials were placed approximately 5 cm from the
light). The resulting reaction mixture was concentrated first and
diluted with CH2Cl2. Aqueous solution of 20% Na2S2O3 was added,
and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
Combined organic extracts were washed with brine, dried over
MgSO4, and filtered. The organic layer was concentrated under
reduced pressure and purified on silica gel using hexanes/EtOAc as
eluent (gradient from 100/0 to 80/20).
General Procedure for One-Pot β C−H Amination of
Secondary Alcohols (GP2). GP2 is the same as GP1 except for
the following changes: 3 (74.7 mg, 0.3 mmol, 3.0 equiv) was used,
and the hemiaminal formation was allowed to stir longer until
disappearance of alcohol was observed by TLC (up to 24 h).
3-Hexyl-8-methyl-9b-(trifluoromethyl)-2,3-dihydro-9bH-benzo-
[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (6). Following GP1, the
compound was formed using 1-octanol (15.0 μL, 0.1 mmol, 1 equiv).
The title compound was obtained as a white solid (25.3 mg, 67%
yield, >20:1 dr). MP: 67.7−68.5 °C; TLC: Rf = 0.53 in 20% EtOAc/
hexanes; IR (neat) ν (cm−1): 2963, 2923, 2893, 2859, 1600, 1469,
1385, 1335, 1250, 1182, 1169; 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.68 (d, J = 8.0 Hz, 1H), 7.52−7.49 (m, 2H), 4.30 (quint, J =
6.7 Hz, 1H), 4.24−4.20 (m, 1H), 4.10−4.06 (m, 1H), 2.50 (s, 3H),
1.89−1.81 (m, 1H), 1.57−1.29 (m, 8H), 0.90 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ (ppm): 145.6, 134.8, 133.7, 132.1, 125.9,
123.0 (q, J1CF = 287.3 Hz), 121.5, 97.5 (q, J2CF = 34.4 Hz), 74.7, 61.7,
33.9, 31.7, 29.1, 26.5, 22.7, 22.0, 14.2; 19F NMR (CDCl3, 376 MHz) δ
(ppm): −79.1; HRMS (m/z ESI-TOF): calculated for
C17H22F3NO3SNa+ [M + Na]+ 400.1165, found 400.1171.
−79.2; HRMS (m/z ESI-TOF): calculated for C12H12F3NO3SNa+ [M
+ Na]+ 330.0388, found 330.0375.
8-(tert-Butyl)-2-methyl-11a-(trifluoromethyl)-6a,7,8,9,10,10a-
hexahydro-11aH-benzo[d]benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-
Dioxide (8). Following GP2, the compound was formed using cis-4-
terbutylcyclohexanol (15.6 mg, 0.1 mmol, 1 equiv). The title
compound was obtained as a white solid (75% yield, >20:1 dr −
NMR). TLC: Rf = 0.30 in 10% EtOAc/hexanes; IR (neat) ν (cm−1):
1
2926, 1600, 1454, 1342, 1250, 1185, 1151; H NMR (CDCl3, 400
MHz) δ (ppm): 7.69 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.50 (d, J =
8.0 Hz, 1H), 4.35−4.29 (m, 1H), 3.74−3.72 (m, 1H), 2.51 (s, 3H),
2.25−2.20 (m, 1H), 2.10−2.04 (m, 1H), 1.63−1.52 (m, 4H), 1.04−
0.97 (m, 1H), 0.89 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm):
145.5, 136.4, 133.6, 133.5, 126.0, 123.8, 122.5 (q, J1 = 276.2 Hz),
CF
121.8, 121.0, 97.0 (q, J2 = 35.2 Hz), 76.5, 61.8, 45.8, 32.6, 30.1,
CF
29.9, 27.8, 27.6, 27.5, 27.2, 22.0, 20.9; 19F NMR (CDCl3, 565 MHz) δ
(ppm): −78.6. HRMS (m/z ESI-TOF): calculated for
C19H24F3N2O3SNa+ ([M + Na]+) 426.1321, found 426.1309.
8-Methyl-3-phenyl-9b-(trifluoromethyl)-2,3-dihydro-9bH-benzo-
[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (9). Following GP1, the
compound was formed using 2-phenylethanol (12 μL, 0.1 mmol, 1
equiv). The title compound was obtained as an off-white solid (26.3
mg, 66% yield, >20:1 dr). MP: 126.0−128.0 °C; TLC: Rf = 0.15 in
10% EtOAc/pentane; IR (neat) ν (cm−1): 3067, 3038, 2968, 2911,
1599, 1495, 1476, 1456, 1337, 1305, 1255, 1166, 1117, 974, 816; 1H
NMR (CDCl3, 600 MHz) δ (ppm): 7.70 (d, J = 7.9 Hz, 1H), 7.53
(dd, J = 23.7, 8.7 Hz, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.34 (d, J = 7.3
Hz, 1H), 5.26 (ap t, J = 8.3 Hz, 1H), 4.68 (ap t, J = 8.6 Hz, 1H), 4.38
(ap t, J = 8.6 Hz, 1H), 2.53 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
(ppm): 145.7, 136.1, 134.6, 133.9, 132.0, 129.2, 128.8, 128.1, 126.8,
125.9, 125.9, 123.4 (q, J1 = 288.0 Hz), 121.7, 97.8 (q, J2 = 34.1
CF
CF
Hz), 64.7, 22.0; 19F NMR (CDCl3, 565 MHz) δ (ppm): −78.4;
HRMS (m/z ESI-TOF): calculated for C17H14F3NO3SNa ([M +
Na]+) 392.0544, found 392.0549.
3-(2-Chlorophenyl)-8-methyl-9b-(trifluoromethyl)-2,3-dihydro-
9bH-nenzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (10). Follow-
ing GP1, the compound was formed using 2-(2-chlorophenyl)ethan-
1-ol (13.2 μL, 0.1 mmol, 1 equiv). The title compound was obtained
as an off-white solid (66% yield, 4:1 dr − NMR). MP: 150.0−151.0
°C; TLC: Rf = 0.13 in 10% EtOAc/pentane; IR (neat) ν (cm−1):
2965, 2914, 1574, 1475, 1335, 1182, 1168, 1032, 996; 1H NMR
(CDCl3, 600 MHz) δ (ppm): 7.92 (d, J = 7.8 Hz, 1H), 7.71 (d, J =
7.7 Hz, 1H), 7.57−7.55 (m, 2H), 7.41−7.38 (m, 2H), 7.31−7.29 (m,
1H), 5.65 (ap t, J = 8.3 Hz, 1H), 5.02−4.99 (m, 1H), 4.25−4.22 (m,
1H), 2.54 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm): 145.8,
134.8, 134.4, 134.0, 132.3, 131.7, 129.8, 129.7, 128.0, 127.7, 125.9,
123.4 (q, J1CF = 290.1 Hz), 121.8, 97.6 (q, J2CF = 33.9 Hz), 76.3, 62.2,
22.1; 19F NMR (CDCl3, 565 MHz) δ (ppm): −78.4; HRMS (m/z
ESI-TOF): calculated for C17H13ClF3NO3SNa+ ([M + Na]+)
426.0154, found 426.0144.
8-Methyl-9b-(trifluoromethyl)-3-(2-(trifluoromethyl)phenyl)-2,3-
dihydro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (11).
Following GP1, the compound was formed using 2-(2-
(trifluoromethyl)phenyl)ethan-1-ol (15.2 μL, 0.1 mmol, 1 equiv).
The title compound was obtained as an off-white solid (21.9 mg, 50%
yield, 5:1 dr). MP: 138.0−140.0 °C; TLC: Rf = 0.15 in 10% EtOAc/
pentane; IR (neat) ν (cm−1): 2960, 2915, 1600, 1455, 1340, 1313,
1
3,8-Dimethyl-9b-(trifluoromethyl)-2,3-dihydro-9bH-benzo[4,5]-
isothiazolo[3,2-b]oxazole 5,5-Dioxide (7). Following GP1, the
compound was formed using 1-propanol (7.5 μL, 0.1 mmol, 1
equiv), but the amination proceeded in only 8 h (rather than 24 h).
The title compound was obtained as a white solid (62% yield, >20:1
dr − NMR). MP: 105.0−107.0 °C; TLC: Rf = 0.41 in 20% EtOAc/
hexanes; IR (neat) ν (cm−1): 2925, 2860, 1599, 1469, 1384, 1322,
1250, 1182, 1140; 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.67 (d, J =
8.0 Hz, 1H), 7.52−7.49 (m, 2H), 4.44−4.35 (m, 1H), 4.26 (ap t, J =
7.5 Hz, 1H), 4.04 (ap t, J = 7.7 Hz, 1H), 2.50 (s, 3H), 1.48 (d, J = 6.4
Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm): 145.6, 134.7, 133.7,
132.1, 125.8, 123.1 (q, J1 = 287.0 Hz), 121.5, 97.5 (q, J2 = 34.1
1255, 1183, 1116, 975, 820; H NMR (CDCl3, 600 MHz) δ (ppm):
8.20 (d, J = 8.1 Hz, 1H), 7.72−7.68 (m, 3H), 7.52−7.55 (m, 2H),
7.48 (t, J = 7.7 Hz, 1H), 5.63 (ap t, J = 8.5 Hz, 1H), 4.80 (ap t, J = 7.9
Hz, 1H), 4.22 (ap t, J = 9.2 Hz, 1H), 2.54 (s, 3H); 13C NMR (CDCl3,
150 MHz) δ (ppm): 145.9, 134.7, 134.4, 134.0, 133.3, 131.9, 128.8,
128.1 (J2 = 30.2 Hz), 128.1, 126.4 (J3 = 5.9 Hz), 125.9, 123.5
CF
CF
(J1 = 288.5 Hz), 124.3 (J1 = 270.9 Hz), 121.8, 97.5 (J2 = 35.9
CF
CF
CF
Hz), 77.8, 61.9, 22.0; 19F NMR (CDCl3, 565 MHz) δ (ppm): −62.7,
−78.4; HRMS (m/z ESI-TOF): calculated for C18H13F6NO3SNa+
([M + Na]+) 460.0418, found 460.0416.
3-(3-Methoxyphenyl)-8-methyl-9b-(trifluoromethyl)-2,3-dihy-
dro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (12). Fol-
lowing GP1, the compound was formed using 2-(3-methoxyphenyl)-
CF
CF
Hz), 75.9, 57.5, 21.9, 19.3; 19F NMR (CDCl3, 376 MHz) δ (ppm):
E
DOI: 10.1021/acs.joc.9b02052
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ethan-1-ol (14.2 μL, 0.1 mmol, 1 equiv). The title compound was
obtained as a white solid (40% yield, 4:1 dr − NMR). MP: 129.0−
131.0 °C; TLC: Rf = 0.36 in 20% EtOAc/hexanes; IR (neat) ν
(cm−1): 2923, 1604, 1494, 1470, 1437, 1371, 1336, 1307, 1276, 1256,
Following GP1, the compound was formed using 2-(4-
methoxyphenyl)ethan-1-ol (15.2 mg, 0.1 mmol, 1 equiv). The title
compound was obtained as an off-white solid (55% yield, 1.5:1 dr −
NMR). MP: 110.0−112.0 °C; TLC: Rf = 0.15 in 10% EtOAc/
pentane; IR (neat) ν (cm−1): 2959, 2925, 2852, 1613, 1516, 1463,
1
1224, 1184; H NMR (CDCl3, 400 MHz) δ (ppm): 7.71 (d, J = 8.1
1
Hz, 1H), 7.56−7.54 (m, 2H), 7.34−7.30 (m, 1H), 7.09−7.06 (m,
2H), 6.90−6.87 (m, 1H), 5.24 (ap t, J = 9.0 Hz, 1H), 4.70−4.65 (m,
1H), 4.39−4.34 (m, 1H), 3.83 (s, 3H), 2.53 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ (ppm): 160.3, 145.7, 137.7, 134.6, 133.9, 131.9,
1333, 1181, 1109, 828, 760; H NMR (CDCl3, 600 MHz) δ (ppm):
Major diastereomer - 7.69 (d, J = 8.0 Hz, 1H), 7.60−7.53 (m, 2H),
7.30 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.30 (dd, J = 8.9,
5.7 Hz, 1H), 4.64−4.60 (m, 1H), 4.41 (ap t, J = 8.4 Hz, 1H), 3.81 (s,
3H), 2.53 (s, 3H). Minor diastereomer - 7.78 (d, J = 8.3 Hz, 1H),
7.60−7.53 (m, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.8 Hz,
1H), 6.94 (d, J = 8.9 Hz, 2H), 5.20 (ap t, J = 8.4 Hz, 1H), 4.64−4.60
(m, 1H), 4.36 (ap t, J = 8.7 Hz, 1H), 3.82 (s, 3H), 2.53 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ (ppm): 160.1, 160.0, 145.7, 145.5, 135.6,
134.7, 133.9, 133.5, 132.0, 130.7, 129.6, 128.3, 127.8, 125.9, 125.7,
123.6, 123.4 (J1CF = 289.7 Hz), 123.2 (J1CF = 287.1 Hz), 121.7, 121.0,
114.6, 114.1, 97.6 (J2CF = 34.4 Hz), 96.9 (J2CF = 34.4 Hz), 72.7, 65.4,
34.5, 55.5, 55.4, 22.0, 21.9; 19F NMR (CDCl3, 377 MHz) δ (ppm):
Major diastereomer - 78.9, Minor diastereomer - 78.5; HRMS (m/z
ESI-TOF): calculated for C18H16F3NO4SNa+ ([M + Na]+) 422.0650,
found 422.0637.
130.3, 129.8, 125.9, 123.3 (q, J1 = 284.1 Hz), 121.7, 119.0, 114.3,
CF
112.3, 97.8 (q, J2 = 32.6 Hz), 64.5, 55.4, 22.0; 19F NMR (CDCl3,
CF
565 MHz) δ (ppm): Major diastereomer - 78.4, Minor diastereomer -
78.9; HRMS (m/z ESI-TOF): calculated for C18H16F3NO4SNa+ ([M
+ Na]+) 422.0650, found 422.0643.
8-Methyl-9b-(trifluoromethyl)-3-(3-(trifluoromethyl)phenyl)-2,3-
dihydro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (13).
Following GP1, the compound was formed using 2-(3-
(trifluoromethyl)phenyl)ethan-1-ol (15.2 μL, 0.1 mmol, 1 equiv).
The title compound was obtained as an off-white solid (20.7 mg, 47%
yield, >20:1 dr). MP: 141.0−142.0 °C; TLC: Rf = 0.31 in 20%
EtOAc/pentane; IR (neat) ν (cm−1): 2919, 2850, 1735, 1599, 1457,
1378, 1329, 1270, 1254, 1223; 1H NMR (CDCl3, 600 MHz) δ
(ppm): 7.80 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.68 (s,
1H), 7.64 (d, J = 8.1 Hz, 1H), 7.59−7.55 (m, 3H), 5.32 (ap t, J = 8.2
Hz, 1H), 4.73−4.69 (m, 1H), 4.40−4.35 (m, 1H), 2.54 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ (ppm): 146.0, 137.4, 134.4, 134.1, 131.7,
131.6 (q, J2CF = 32.6 Hz), 130.2, 129.4, 125.9, 125.8 (J3CF = 3.7 Hz),
(3R,9bR)-8-Methyl-3-(p-tolyl)-9b-(trifluoromethyl)-2,3-dihydro-
9bH-benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (17). Follow-
ing GP1, the compound was formed using 2-(p-tolyl)ethan-1-ol (13.8
μL, 0.1 mmol, 1 equiv). The title compound was obtained as an off-
white solid (80% yield, 2:1 dr − NMR). MP: 130.0−132.0 °C; TLC:
Rf = 0.18 in 10% EtOAc/pentane; IR (neat) ν (cm−1): 2961, 2924,
1
124.0 (q, J1CF = 272.5 Hz), 123.7 (q, J3CF = 3.7 Hz), 123.3 (q, J1
=
1514, 1334, 1224, 1181, 992, 816; H NMR (CDCl3, 600 MHz) δ
CF
287.8 Hz), 121.8, 97.9 (q, J2CF = 34.5 Hz), 76.9, 64.1, 22.0; 19F NMR
(CDCl3, 565 MHz) δ (ppm): −62.7, −78.4; HRMS (m/z ESI-TOF):
calculated for C18H13F6NO3SNa+ ([M + Na]+) 460.0418, found
460.0415.
(ppm): Major diastereomer - 7.69 (d, J = 8.0 Hz, 1H), 7.56−7.47 (m,
2H), 7.40 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 5.22 (ap t, J =
8.5 Hz, 1H), 4.67−4.61 (m, 1H), 4.43−4.33 (m, 1H), 2.53 (s, 3H),
2.37 (s, 3H); Minor diastereomer - 7.61 (bs, 1H), 7.56−7.47 (m, 2H),
7.27 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 5.31 (dd, J = 8.6,
5.8 Hz, 1H), 4.67−4.61 (m, 1H), 2.53 (s, 3H), 2.35 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ (ppm): 145.7, 145.6, 138.8, 138.6, 135.5,
134.7, 133.5, 133.0, 132.0, 130.7, 129.9, 129.4, 129.0, 128.0, 126.8,
125.9, 125.7, 123.4 (J1CF = 289.3 Hz), 123.2 (J1CF = 286.2 Hz), 121.7,
121.0, 97.7 (J2 = 34.4 Hz), 96.9 (J2 = 32.9 Hz), 72.7, 65.5, 64.7,
8-Methyl-9b-(trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)-2,3-
dihydro-9bH-benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (14).
Following GP1, the compound was formed using 2-(4-
(trifluoromethyl)phenyl)ethan-1-ol (15.2 μL, 0.1 mmol, 1 equiv).
The title compound was obtained as an off-white solid (30.2 mg, 69%
yield, >20:1 dr). MP: 138.0−140.0 °C; TLC: Rf = 0.38 in 20%
EtOAc/pentane; IR (neat) ν (cm−1): 2914, 1623, 1600, 1478, 1428,
CF
CF
22.0, 21.9, 21.4, 21.3; 19F NMR (CDCl3, 565 MHz) δ (ppm): Major
diastereomer - 78.4, Minor diastereomer - 78.9; HRMS (m/z ESI-
TOF): calculated for C18H16F3NO3SNa+ ([M + Na]+) 406.0701,
found 406.0688.
1
1337, 1323, 1303, 1257, 1225, 1175, 1149, 1104; H NMR (CDCl3,
400 MHz) δ (ppm): 7.72−7.55 (m, 7H), 5.33 (ap t, J = 8.0 Hz, 1H),
4.72 (ap t, J = 8.0 Hz, 1H), 4.37 (ap t, J = 8.8 Hz, 1H), 2.54 (s, 3H);
13C NMR (CDCl3, 150 MHz) δ (ppm): 160.3, 146.0, 140.3, 134.3,
134.1, 131.7, 131.1 (q, J2 = 32.7 Hz), 127.2, 126.2 (q, J3 = 3.9
8-Methyl-3-(pyridin-2-yl)-9b-(trifluoromethyl)-2,3-dihydro-9bH-
benzo[4,5]isothiazolo[3,2-b] Oxazole 5,5-Dioxide (18). Following
GP1, the compound was formed using 2-pyridineethanol (11.3 μL,
0.1 mmol, 1 equiv), but the amination proceeded in only 8 h (rather
than 24 h). The title compound was obtained as an off-white solid
(49% yield, 6:1 dr − NMR). MP: 125.0−127.0 °C; TLC: Rf = 0.08 in
10% EtOAc/pentane; IR (neat) ν (cm−1): 3022, 2963, 2926, 2854,
CF
CF
Hz), 125.9, 125.9, 124.1 (q, J1 = 272.8 Hz), 123.3 (q, J1 = 288.5
CF
CF
Hz), 121.8, 97.9 (q, J2 = 34.2 Hz), 64.0, 22.0; 19F NMR (CDCl3,
CF
377 MHz) δ (ppm): −62.7, −78.4; HRMS (m/z ESI-TOF):
calculated for C18H13F6NO3SNa+ ([M + Na]+) 460.0418, found
460.0415.
1
1598, 1475, 1355, 1215, 1183, 748; H NMR (CDCl3, 600 MHz) δ
3-(4-Fluorophenyl)-8-methyl-9b-(trifluoromethyl)-2,3-dihydro-
9bH-benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (15). Follow-
ing GP1, the compound was formed using 2-(4-fluorophenyl)ethan-1-
ol (12.5 μL, 0.1 mmol, 1 equiv). The title compound was obtained as
an off-white solid (34.8 mg, 49% yield, 5:1 dr − NMR). MP: 136.0−
138.0 °C; TLC: Rf = 0.13 in 10% EtOAc/pentane; IR (neat) ν
(cm−1): 2963, 2917, 2851, 1735, 1606, 1512, 1334, 1181, 1151, 976,
835. 1H NMR (CDCl3, 600 MHz) δ (ppm): 7.70 (d, J = 8.2 Hz, 1H),
7.57−7.47 (m, 4H), 7.13−7.08 (m, 2H), 5.23 (ap t, J = 8.4 Hz, 1H),
4.68−4.63 (m, 1H), 4.37−4.32 (m, 1H), 2.53 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ (ppm): 163.9, 162.2, 145.8, 145.7, 135.5, 134.5,
(ppm): 8.57−8.55 (m, 1H), 7.82−7.78 (m, 2H), 7.75 (d, J = 7.9 Hz,
1H), 7.58−7.56 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 5.52 (ap t, J = 7.4
Hz, 1H), 4.80−4.72 (m, 2H), 2.54 (s, 3H); 13C NMR (CDCl3, 150
MHz) δ (ppm): 157.3, 149.4, 146.0, 137.6, 134.4, 133.9, 131.8, 125.9,
123.1 (q, J1CF = 287.1 Hz), 123.1, 121.7, 121.0, 96.1 (J2CF = 32.7 Hz),
75.5, 64.1, 22.0; 19F NMR (CDCl3, 565 MHz) δ (ppm): −78.7;
HRMS (m/z ESI-TOF): calculated for C16H14F3N2O3S+ ([M + H]+)
371.0672, found 371.0674.
3-Isopropyl-8-methyl-9b-(trifluoromethyl)-2,3-dihydro-9bH-
benzo[4,5]isothiazolo[3,2-b]oxazole 5,5-Dioxide (19). Following
GP1, the compound was formed using 3-methyl-1-butanol (11.0
μL, 0.1 mmol, 1 equiv). The title compound was obtained as a white
solid (37% yield, 2.3:1, β:γ − NMR). MP: 97.0−99.0 °C; TLC: Rf =
0.44 in 20% EtOAc/hexanes; IR (neat) ν (cm−1): 2968, 2923, 2851,
134.0, 133.6, 132.3, 131.9, 131.6, 130.7, 130.0 (d, J2 = 9.1 Hz),
CF
128.7 (d, J2 = 8.6 Hz), 125.9, 125.8, 123.4 (q, J1 = 287.8 Hz),
CF
123.1 (q, J1CCFF = 289.2 Hz), 121.8, 121.5, 121.1, 116.2 (d, J1CF = 21.1
Hz), 115.8 (d, J1 = 21.3 Hz), 97.7 (q, J2 = 34.1 Hz), 72.9, 67.8,
CF
CF
1
65.0, 64.1, 22.1, 22.0; 19F NMR (CDCl3, 565 MHz) δ (ppm): Major
diastereomer - 78.5, −113.3, Minor diastereomer - 78.9−112.3;
HRMS (m/z ESI-TOF): calculated for C17H13F4NO3SNa+ ([M +
Na]+) 410.0450, found 410.0437.
1598, 1467, 1341, 1322, 1304, 1256, 1173, 1158; H NMR (CDCl3,
400 MHz) δ (ppm): 7.70 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.2 Hz,
1H), 7.49 (s, 1H), 4.25−4.20 (m, 2H), 4.01−3.96 (m, 1H), 2.50 (s,
3H), 1.97−1.91 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.7
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 145.6, 134.6, 133.7,
131.9, 125.7, 123.1 (q, J1 = 287.2 Hz), 121.6, 97.7 (q, J2 = 34.0
3-(4-Methoxyphenyl)-8-methyl-9b-(trifluoromethyl)-2,3-dihy-
dro-9bH-benzo[4,5]isothiazolo [3,2-b]oxazole 5,5-Dioxide (16).
CF
CF
F
DOI: 10.1021/acs.joc.9b02052
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz), 73.6, 67.5, 31.8, 29.9, 22.0, 20.5, 19.0; 19F NMR (CDCl3, 376
MHz) δ (ppm): −79.0; HRMS (m/z ESI-TOF): calculated for
C14H16F3NO3SNa+ [M + Na]+ 358.0695, found 358.0678.
REFERENCES
■
(1) (a) Chen, K.; Baran, P. S. Total Synthesis of Eudesmane
Terpenes by Site-Selective C-H Oxidations. Nature 2009, 459, 824−
828. (b) Mo, F.; Tabor, J. R.; Dong, G. Alcohols or Masked Alcohols
as Directing Groups for C-H Bond Functionalization. Chem. Lett.
2014, 43, 264−271.
(2) Reviews: (a) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed
Ligand-Directed C-H Functionalization Reactions. Chem. Rev. 2010,
110, 1147−1169. (b) Du Bois, J. Rhodium-Catalyzed C−H
Amination. An Enabling Method for Chemical Synthesis. Org. Process
Res. Dev. 2011, 15, 758−762. (c) He, J.; Wasa, M.; Chan, K. S. L.;
Shao, Q.; Yu, J. Q. Palladium-Catalyzed Transformations of Alkyl C-
H Bonds. Chem. Rev. 2017, 117, 8754−8786. (d) Xu, Y.; Dong, G.
sp3 C-H Activation via Exo-Type Directing Groups. Chem. Sci. 2018,
9, 1424−1432.
1-(8-Methyl-5,5-dioxido-9b-(trifluoromethyl)-2,3-dihydro-9bH-
benzo[4,5]isothiazolo[3,2-b]oxazol-3-yl)propan-2-one (20). Fol-
lowing GP1, the compound was formed using 3-acetyl-1-propanol
(10 μL, 0.1 mmol, 1 equiv). The title compound was obtained as an
off-white solid (33% yield, >20:1 dr − NMR); TLC: Rf = 0.21 in 20%
in EtOAc/hexanes; IR (neat) ν (cm−1): 2923, 1716, 1600, 1417,
1
1358, 1282, 1249, 1179, 1160, 1118, 1057; H NMR (CDCl3, 400
MHz) δ (ppm): 7.68 (d, J = 8.0 Hz, 1H), 7.53−7.50 (m, 2H), 4.69−
4.63 (m, 1H), 4.41−4.37 (m, 1H), 4.04 (dd, J = 8.7, 6.0 Hz, 1H), 3.24
(dd, J = 18.4, 4.5 Hz, 1H), 2.91 (dd, J = 18.4, 9.9 Hz, 1H), 2.54 (s,
3H), 2.22 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 205.8,
146.2, 145.8, 134.6, 133.8, 133.2, 131.8, 129.9, 129.7, 125.9 (q, J3
=
CF
1.8 Hz), 125.7 (q, J1 = 276.7 Hz), 124.9 (q, J3 = 1.6 Hz), 122.3
CF
CF
121.9 (q, J1CF = 282.0 Hz), 121.5, 97.1 (q, J2CF = 34.2 Hz), 74.6, 57.0,
47.9, 30.3, 22.0, 21.9; 19F NMR (CDCl3, 377 MHz) δ (ppm): −79.3;
HRMS (m/z ESI-TOF): calculated for C14H14F3NO4SNa+ [M + Na]+
372.0488, found 372.0474.
(3) Pioneering examples of alcohol-directed C−H functionalization:
(a) Espino, C. G.; Du Bois, J. A Rh-Catalyzed C-H Insertion Reaction
for the Oxidative Conversion of Carbamates to Oxazolidinones.
Angew. Chem., Int. Ed. 2001, 40, 598−600. (b) Fraunhoffer, K. J.;
White, M. C. Syn-1,2-Amino Alcohols via Diastereoselective Allylic C-
H Amination. J. Am. Chem. Soc. 2007, 129, 7274−7276. (c) Huang,
C.; Gevorgyan, V. TBDPS and Br-TBDPS Protecting Groups as
Efficient Aryl Group Donors in Pd-Catalyzed Arylation of Phenols
and Anilines. J. Am. Chem. Soc. 2009, 131, 10844−10845. (d) Rice, G.
T.; White, M. C. Allylic C-H Amination for the Preparation of Syn
−1,3-Amino Alcohol Motifs. J. Am. Chem. Soc. 2009, 131, 11707−
11711. (e) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. Silanol: A
Traceless Directing Group for Pd-Catalyzed o-Alkenylation of
Phenols. J. Am. Chem. Soc. 2011, 133, 12406−12409. (f) Simmons,
E. M.; Hartwig, J. F. Catalytic Functionalization of Unactivated
Primary C-H Bonds Directed by an Alcohol. Nature 2012, 483, 70−
73. (g) Ren, Z.; Mo, F.; Dong, G. Catalytic Functionalization of
Unactivated sp3 C-H Bonds via Exo-Directing Groups: Synthesis of
Chemically Differentiated 1,2-Diols. J. Am. Chem. Soc. 2012, 134,
16991−16994. (h) Lee, S.; Lee, H.; Tan, K. L. Meta-Selective C-H
Functionalization Using a Nitrile-Based Directing Group and
Cleavable Si-Tether. J. Am. Chem. Soc. 2013, 135, 18778−18781.
(i) Xu, Y.; Yan, G.; Ren, Z.; Dong, G. Diverse sp3 C-H
Functionalization through Alcohol β-Sulfonyloxylation. Nat. Chem.
2015, 7, 829−834.
(4S,10bR)-9-Methyl-4-phenyl-10b-(trifluoromethyl)-3,4-dihydro-
2H,10bH-benzo[4,5]isothiazolo[3,2-b][1,3]oxazine 6,6-Dioxide
(21). Following GP1, the compound was formed using 3-phenyl-
propanol (13.6 μL, 0.1 mmol, 1 equiv). The title compound was
obtained as a white solid (36% yield, 1:2.6, β:γ − NMR). TLC: Rf =
0.51 in 10% EtOAc/hexanes; IR (neat) ν (cm−1): 2923, 2852, 1696,
1
1602, 1458, 1336, 1253, 1185, 1150, 1115, 1081; H NMR (CDCl3,
400 MHz) δ (ppm): β-amination - 7.78 (d, J = 7.9 Hz, 1H), 7.56−
7.54 (m, 1H), 7.52 (m, 1H), 7.50−7.45 (m, 2H), 7.42−7.34 (m, 3H),
5.39 (ap t, J = 8.4 Hz, 1H), 4.19−4.14 (m, 1H), 3.90−3.80 (m, 1H),
2.52 (s, 3H), 2.47−2.42 (m, 1H); γ-amination - 7.76 (d, J = 7.9 Hz,
1H), 7.56−7.54 (m, 1H), 7.50−7.45 (m, 3H), 7.42−7.34 (m, 3H),
5.11−5.06 (m, 2H), 3.90−3.80 (m, 2H), 2.54−2.52 (m, 1H), 2.51 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ (ppm): 145.6, 134.8, 133.7,
132.1, 125.9, 123.0 (q, J1 = 287.3 Hz), 121.5, 97.5 (q, J2 = 34.4
CF
Hz), 74.7, 61.7, 33.9, 31.7, 29.1, 26.5, 22.7, 22.0, 14.2; 1C9FF NMR
(CDCl3, 565 MHz) δ (ppm): β-amination - 77.7, γ-amination - 79.3;
HRMS (m/z ESI-TOF): calculated for C18H16F3NO3SNa+ ([M +
Na]+) 406.0695, found 406.0682.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b02052.
■
(4) Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. Remote C-H
Functionalization via Selective Hydrogen Atom Transfer. Synthesis
2018, 50, 1569−1586.
S
̌
̌
́
(5) HAT Reviews: (a) Cekovic, Z. Reactions of δ-Carbon Radicals
Generated by 1,5-Hydrogen Transfer to Alkoxyl Radicals. Tetrahedron
2003, 59, 8073−8090. (b) Chiba, S.; Chen, H. Sp3 C−H Oxidation
by Remote H-Radical Shift with Oxygen- and Nitrogen-Radicals: A
Recent Update. Org. Biomol. Chem. 2014, 12, 4051−4060. (c) Li, W.;
Xu, W.; Xie, J.; Yu, S.; Zhu, C. Distal Radical Migration Strategy: An
Emerging Synthetic Means. Chem. Soc. Rev. 2018, 47, 654−667.
(6) Pioneering examples of intramolecular HAT from alcohols:
(a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. A
New Photochemical Reaction. J. Am. Chem. Soc. 1960, 82, 2640−
2641. (b) Greene, F. D.; Savitz, M. L.; Lau, H. H.; Osterholtz, D.;
Smith, W. N. Decomposition of Tertiary Alkyl Hypochlorites. J. Am.
Chem. Soc. 1961, 83, 2196−2198. (c) Walling, C.; Padwa, A.
Intramolecular Chlorination with Long Chain Hypochlorites. J. Am.
Chem. Soc. 1961, 83, 2207−2208.
1H, 13C, and 19F NMR spectral data (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: nagib.1@osu.edu.
■
ORCID
David A. Nagib: 0000-0002-2275-6381
Author Contributions
†K.M.N., R.K.T., A.V.: These authors contributed equally.
Notes
The authors declare no competing financial interest.
(7) Pioneering examples of radical chaperones for remote HAT of
alcohols: (a) Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu,
S.; Washburn, W. Remote Oxidation of Steroids by Photolysis of
Attached Benzophenone Groups. J. Am. Chem. Soc. 1973, 95, 3251−
3262. (b) Breslow, R.; Corcoran, R. J.; Snider, B. B.; Doll, R. J.;
Khanna, P. L.; Kaleya, R. Selective Halogenation of Steroids Using
Attached Aryl Iodide Templates. J. Am. Chem. Soc. 1977, 99, 905−
915.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (NIH R35
GM119812), National Science Foundation (NSF CAREER
1654656), and American Chemical Society Petroleum
Research Fund for financial support. Structural data was
collected by Dr Antonio DiPasquale at the UC Berkeley X-ray
Crystallography Facility (supported by NIH S10-RR027172).
R.K.T. is supported by an NSF GRFP Fellowship.
(8) Recent examples of radical chaperones for HAT of alcohols:
(a) Chen, K.; Richter, J. M.; Baran, P. S. 1,3-Diol Synthesis via
Controlled, Radical-Mediated C-H Functionalization. J. Am. Chem.
G
DOI: 10.1021/acs.joc.9b02052
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Soc. 2008, 130, 7247−7249. (b) Voica, A.-F.; Mendoza, A.;
Gutekunst, W. R.; Fraga, J. O.; Baran, P. S. Guided Desaturation of
Unactivated Aliphatics. Nat. Chem. 2012, 4, 629−635. (c) Parasram,
M.; Chuentragool, P.; Sarkar, D.; Gevorgyan, V. Photoinduced
Formation of Hybrid Aryl Pd-Radical Species Capable of 1,5-HAT:
Selective Catalytic Oxidation of Silyl Ethers into Silyl Enol Ethers. J.
Am. Chem. Soc. 2016, 138, 6340−6343. (d) Ozawa, J.; Tashiro, M.;
Ni, J.; Oisaki, K.; Kanai, M. Chemo- and Regioselective Oxygenation
of C(sp3)-H Bonds in Aliphatic Alcohols Using a Covalently Bound
Directing Activator and Atmospheric Oxygen. Chem. Sci. 2016, 7,
1904−1909. (e) Short, M. A.; Blackburn, J. M.; Roizen, J. L.
Sulfamate Esters Guide Selective Radical-Mediated Chlorination of
Aliphatic C-H Bonds. Angew. Chem., Int. Ed. 2018, 57, 296−299.
(f) Mou, X. Q.; Chen, X. Y.; Chen, G.; He, G. Radical-Mediated
Intramolecular β-C(sp3)-H Amidation of Alkylimidates: Facile
Synthesis of 1,2-Amino Alcohols. Chem. Commun. 2018, 54, 515−
518. (g) Kumar, Y.; Jaiswal, Y.; Kumar, A. Visible-Light-Mediated
Remote γ-C(sp3)-H Functionalization of Alkylimidates: Synthesis of
4-Iodo-3,4-Dihydropyrrole Derivatives. Org. Lett. 2018, 20, 4964−
4969. (h) Shaw, M.; Kumar, A. Visible-Light-Mediated β-C(sp3)-H
Amination of Glycosylimidates: En Route to Oxazoline-Fused/Spiro
Nonclassical Bicyclic Sugars. Org. Lett. 2019, 21, 3108−3113.
(9) (a) Wappes, E. A.; Nakafuku, K. M.; Nagib, D. A. Directed β C−
H Amination of Alcohols via Radical Relay Chaperones. J. Am. Chem.
Soc. 2017, 139, 10204−10207. (b) Wappes, E. A.; Vanitcha, A.;
Nagib, D. A. β C-H Di-Halogenation via Iterative Hydrogen Atom
Transfer. Chem. Sci. 2018, 9, 4500−4504. (c) Nakafuku, K. M.; Fosu,
S. C.; Nagib, D. A. Catalytic Alkene Difunctionalization via Imidate
Radicals. J. Am. Chem. Soc. 2018, 140, 11202−11205. (d) Stateman,
L. M.; Wappes, E. A.; Nakafuku, K. M.; Edwards, K. M.; Nagib, D. A.
Catalytic β C−H Amination via an Imidate Radical Relay. Chem. Sci.
2019, 10, 2693−2699.
C-H Amination: Scope, Mechanism, and Applications. Chem. Rev.
2017, 117, 9247−9301. (f) Blakemore, D. C.; Castro, L.; Churcher, I.;
Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic
Synthesis Provides Opportunities to Transform Drug Discovery. Nat.
Chem. 2018, 10, 383−394.
́
(16) Francisco, C. G.; Herrera, A. J.; Suarez, E. Intramolecular
Hydrogen Abstraction Reaction Promoted by N-Radicals in
Carbohydrates. Synthesis of Chiral 7-Oxa-2-Azabicyclo[2.2.1]-
Heptane and 8-Oxa-6-Azabicyclo[3.2.1]Octane Ring Systems. J.
Org. Chem. 2003, 68, 1012−1017.
(17) Luo, Y. R. Comprehensive Handbook of Chemical Bond Energies;
CRC Press: Boca Raton, FL, 2007.
(10) (a) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. Catalytic
Scaffolding Ligands: An Efficient Strategy for Directing Reactions. J.
Am. Chem. Soc. 2008, 130, 9210−9211. (b) MacDonald, M. J.;
Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. A Catalytic
Tethering Strategy: Simple Aldehydes Catalyze Intermolecular Alkene
Hydroaminations. J. Am. Chem. Soc. 2011, 133, 20100−20103.
(c) Guimond, N.; MacDonald, M. J.; Lemieux, V.; Beauchemin, A. M.
Catalysis through Temporary Intramolecularity: Mechanistic Inves-
tigations on Aldehyde-Catalyzed Cope-Type Hydroamination Lead to
the Discovery of a More Efficient Tethering Catalyst. J. Am. Chem.
Soc. 2012, 134, 16571−16577.
(11) Gandeepan, P.; Ackermann, L. Transient Directing Groups for
Transformative C−H Activation by Synergistic Metal Catalysis. Chem.
2018, 4, 199−222.
(12) Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A.
Triiodide-Mediated δ-Amination of Secondary C-H Bonds. Angew.
Chem., Int. Ed. 2016, 55, 9974−9978.
(13) Zhang, S.; Li, L.; Hu, Y.; Li, Y.; Yang, Y.; Zha, Z.; Wang, Z.
Highly Enantioselective Construction of Fluoroalkylated Quaternary
Stereocenters via Organocatalytic Dehydrated Mannich Reaction of
Unprotected Hemiaminals with Ketones. Org. Lett. 2015, 17, 5036−
5039.
(14) Blanchet, J.; Macklin, T.; Ang, P.; Metallinos, C.; Snieckus, V.
Directed Ortho Metalation-Cross Coupling Strategies. N-Cumyl
Arylsulfonamides. Facile Deprotection and Expedient Route to 7-
and 4,7-Substituted Saccharins. J. Org. Chem. 2007, 72, 3199−3206.
(15) Reviews on C−H amination and drug discovery: (a) Davies, H.
M. L.; Manning, J. R. Catalytic C-H Functionalization by Metal
Carbenoid and Nitrenoid Insertion. Nature 2008, 451, 417−424.
(b) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Metal-Catalyzed
Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C-H
Bonds. Acc. Chem. Res. 2012, 45, 911−922. (c) Jeffrey, J. L.; Sarpong,
R. Intramolecular C(sp3)−H Amination. Chem. Sci. 2013, 4, 4092−
4106. (d) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.;
Krska, S. W. The Medicinal Chemist’s Toolbox for Late Stage
Functionalization of Drug-like Molecules. Chem. Soc. Rev. 2016, 45,
546−576. (e) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed
H
DOI: 10.1021/acs.joc.9b02052
J. Org. Chem. XXXX, XXX, XXX−XXX