Isoindolinones via Copper-Catalyzed Intramolecular Benzylic C-H Sulfamidation

Article abstract of DOI:10.1021/acs.joc.6b02970

2-Benzyl-N-tosylbenzamides and related substrates undergo copper-catalyzed intramolecular sulfamidation at the benzylic methylene to give N-arylsuflonyl-1-arylisoindolinones, which can be N-deprotected using samarium iodide to generate the free 1-arylisoindolinones. Preliminary mechanistic studies indicate that the rate-determining step is not C-H bond cleavage but are instead consistent with slow oxidation of a copper π-arene intermediate.

Full text of DOI:10.1021/acs.joc.6b02970

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Article
Isoindolinones via Copper-Catalyzed
Intramolecular Benzylic C-H Sulfamidation
Robin B. Bedford, John G. Bowen, and Carolina Méndez-Gálvez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02970 • Publication Date (Web): 13 Jan 2017
Downloaded from http://pubs.acs.org on January 13, 2017
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Isoindolinones via Copper-Catalyzed Intramolecular Benzylic
C-H Sulfamidation.
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Robin B. Bedford,* John G. Bowen and Carolina Méndez-Gálvez
School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
KEYWORDS Copper, C-H activation, amidation, sulfamidation.
ABSTRACT: 2-Benzyl-N-tosylbenzamides and related substrates undergo copper-catalyzed intramolecular sulfamidation
at the benzylic methylene to give N-arylsuflonyl-1-arylisoindolinones, which can be N-deprotected using samarium iodide
to generate the free 1-arylisoindolinones. Preliminary mechanistic studies indicate that the rate-determining step is not C-
H
bond cleavage, but are instead consistent with slow oxidation of
a
copper π-arene intermediate.
linones via C-H sulfamidation. Such sulfamidation routes
would be preferable to recently reported catalyzed or cat-
alyst-free amidation reactions with N-aryl substrates,10,11 as
the products should undergo comparatively facile N-
deprotection to yield the free isoindolinones.
Introduction
The isoindolinone core is a privileged structure with ex-
amples showing a range of biological functions and me-
dicinal applications.1 For instance pazinaclone (Figure 1)
has demonstrated anxiolytic properties,2 1 is a dopamine
receptor antagonist,3 2 shows antiretroviral activity,4 le-
nalidomide is used in the treatment of multiple myelo-
ma,5 whilst pestalachloride A, isolated from the fungus
Pestalotiopsis adusta, is reported to have significant anti-
microbial activity.6
Results and Discussion
In the first instance, we undertook an optimisation study,
examining the copper-catalysed12 cyclisation of substrate
3a, which could be easily prepared in one step from ben-
zylbenzoic acid and p-toluenesulfonyl isocyanate, to the
isoindolinone 4a, and the results from this study are
summarised in Table 1.
Table 1. Optimisation of the reaction conditions.
Entry Cu(OTf)2
loading
Oxidant
(equiv.)
Solvent Temp.
Yield
4aa
(v:v)
(°C)
(mol%)
(%)
1
0
PhI(OAc)2
(4)
DCE
120
0
Figure 1. Examples of biologically active isoindolinones.
2
50
“
“
“
“
“
“
“
“
“
41
12
21
0
3b
4c
5
“
“
Catalytic intramolecular sp3-C-H amidation represent an
excellent approach to the synthesis of N-heterocycles,7
and inspired by recent reports of catalytic benzylic C-H
amination,8,9 we wondered whether such an approach
could be applied to the synthesis of N-sufonyl isoindo-
“
“
“
“
HTIB (4)
PIFA (4)
PhI(OAc)2
“
6
“
“
0
7
“
AcOH
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related amidation reactions with N-aryl precursors,10 the
(4)
“
1
2
3
4
5
6
7
8
sulfamidation reaction fails for the substrate 3m. While it
is tempting to conclude from this that two aryl groups are
required at the benzylic center for electronic reasons, this
is clearly not the case in the formation of the 4k. Instead
it appears that a ‘pro-exocyclic’ arene substituent is re-
quired for activity. In addition to the requirement for a
pro-exocyclic arene, it appears that the benzylic site of C-
H functionalization must be incorporated into a structur-
ally rigid framework. Thus while 4k is formed, no cyclisa-
tion is observed with the conformationally flexible sub-
strate 4n, suggesting that the transition state for C-H ac-
tivation requires a sulfonamide-coordinated copper com-
plex to be held in close proximity to the reactive center.
8
“
“
“
“
DCE/
AcOH
(5:1)
“
“
“
“
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“
“
CHCl3/
AcOH
(5:1)
43
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10
11
PhCl/
AcOH
(5:1)
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PhI(OAc)2
(2)
“
12
13
14
20
“
“
“
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“
71
20
0
10
“
Table 2. Successful C-H sulfamidation reactions.a
20
PhCl/
TFA
(5:1)
15
16
“
“
“
“
PhCl/
AcOH
(5:1)
140
100
48
15
“
a. Spectroscopic yield determined by 1H NMR (1,3,5-
C6H3(OMe)3 internal standard). b. Under N2. c. Under O2
In the absence of catalyst, no conversion to the desired
product was observed under air, using four equivalents of
phenylidonium diacetate as the oxidant and 1,2-
dichloroethane (DCE) as the solvent (entry 1). Adding a
high loading of copper (II) triflate (50 mol%, entry 2) led
to a reasonable amount of the desired product, however
the reaction was clearly not catalytic. Repeating the reac-
tion under inert conditions or under O2 proved deleteri-
ous (entries 3 and 4). Replacing PhI(OAc)2 with either
hydroxy(tosyloxy)iodobenzene (HTIB) or PhI(O2CCF3)2
(PIFA) shut down the reaction (entries 5 and 6). While
the use of neat acetic acid as solvent was deleterious (en-
try 7), the use of acetic acid in chlorinated solvents
proved beneficial (entries 8 – 10), with the best activity
obtained using chlorobenzene. With this solvent system,
both the amount of oxidant (2 equiv.) and the catalyst
loading (20 mol%) could be reduced, to give the optimum
conditions indicated in entry 12. Reducing the catalyst
loading further proved to be detrimental, as did either
replacing acetic acid with trifluoroacetic acid (entry 14) or
changing the temperature (entries 15 and 16).
With optimised conditions in hand, we next
briefly explored the range of substrates that undergo the
intramolecular sulfamidation reaction. The successful
results are summarised in Table 2, whilst the substrates
that failed to cyclise are shown in Figure 2.
a. Isolated yields. b. Spectroscopic yield determined
by 1H NMR (1,3,5-C6H3(OMe)3 internal standard).
Diarylmethane-based substrates with electron-
withdrawing and -donating groups on either of the aryl
rings underwent the desired reaction to generate the iso-
indolinones 4a – 4i. Interestingly, C-H functionalization
at a tertiary carbon center was also achieved, yielding the
product 4j in moderate yield. In contrast with Kondo’s
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The role of the electronics of the pro-exocyclic
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3
4
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ring on the rate-determining step of the reaction was
probed by a Hammett analysis of the reactions (Figure 4),
based on the observed maximum rates. The plot against σ
gave a poor correlation whilst that against σ+ gave a mod-
erate R2 of 0.79, and ρ ≈ -1.4.14 This suggests that rate-
determining step involves loss of electron density.15
7
Figure 2. Substrates that failed to cyclize.
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The formation of 4l demonstrates that the reac-
tion can be extended to sulfamidation with the p-nosyl
function. Importantly, both 4l and the related tosyl-
containing 4b undergo ‘instantaneous’ samarium-
mediated deprotection13 to yield the free NH-
isoindolinone, 5 (Scheme 1).
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log(kH/kR)
1.2
Scheme 1. Deprotection of N-sulfonyl isoindolinones.
OMe
1
0.8
Me
F
0.6
0.4
0.2
0
tBu
Cl
H
σ
In order to gain further mechanistic insight, we
followed the formation of the products 4a – f against time
from their precursors 3a – f, and the results of this study
are summarized in Figure 3. It is immediately apparent
that the reaction is favored by electron-donating groups
on the pro-exocyclic arene, with the p-anisyl-based sub-
strate 3c giving by far the highest rate, with maximum
conversion obtained prior to the first sampling point. Fur-
thermore, the reactions with all the other substrates ex-
amined show pronounced induction periods of around 5 –
10 minutes before onset of catalytic activity. Whatever the
catalyst activation process is, it is clear that it is substrate-
dependent.
-0.9
-0.7
-0.5
-0.3
-0.1
0.1
0.3
-0.2
Figure 4. Hammett correlation of maximum rate against
both σ ( ) and σ+ (
)values.
ꢀ
In order to determine whether or not C-H bond-
cleavage features in the rate-limiting step in the catalytic
cycle, we undertook a variety of kinetic isotope effect
studies. Subjecting 3a and its di-deuterated analog 3a-D2
to cyclisation under identical conditions gave the same
rate of formation of the products 3a and 3a-D (kH = 0.062
mM/min; kD = 0.063 mM/min).16 Similarly, a competition
reaction, containing equal amounts of 3a and 3a-D2,
quenched at approximately 30% conversion, gave a prod-
uct mixture containing equal amounts of 4a and 4a-D.
The lack of a kinetic isotope effect in both cases indicates
that C-H bond-cleavage is not involved in the rate-
determining step.17 By contrast, subjecting the 2:1 mixture
of the deuterium-enriched substrate 3a-HD and 3a to the
standard reaction gave a 3:2 ratio of 4a and 4a-D, which
corresponds to a KIE of 1.5. These KIE data are consistent
with the rate-determining step involving substrate inter-
action with the copper and occurring prior to the C-H
functionalization step.17 Consistent with this suggestion is
the observation that the relative rate data above shows a
strong influence of the electronics of the exocyclic arene
on the rate of catalysis.
80
70
60
50
Me
40
30
20
10
0
F
OMe
Cl
H
tBu
0
10
20
30
40
50
60
Time / min
Figure 3. Formation of 4a – f over time. Spectroscopic yields
determined by 1H NMR (1,3,5-C6H3(OMe)3 internal standard).
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Any mechanistic proposal must address the following
observations:
(i)
A pro-exocyclic aryl group is essential for activ-
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ity;
(ii)
The sulfonamide and benzyl functions must be
held proximate within a stereochemically rigid
framework;
(iii)
The rate-determining step is accelerated by in-
creasing electron-density on the pro-exocyclic
aryl ring, but does not involve C-H cleavage
and likely occurs before C-H activation;
I*
(iv)
The high sensitivity of the reaction to the pre-
cise nature of the oxidant.
One possible explanation that can satisfy all of these cri-
teria is the involvement of an ηn-arene-coordinated cop-
per intermediate of the type I (Figure 5), which undergoes
slow oxidation, facilitated by increasing electron-density
on the aryl ring. It has been suggested that a copper
(I)/(III) manifold is active in many C-H functionalization
processes,18 in which case I would contain Cu(I). While
we do not have direct evidence for such a species at pre-
sent, stable Cu(I) arene π-complexes with η1-, η2- and
even η6-arene interactions are known.19 Meanwhile a DFT
examination of a model of I, I* (L = H2O; phenylene
backbone)16 returned a plausible ground-state structure
with an η2-arene interaction (Figure 5).
Figure 5. Top: Putative generalized Cu-arene intermediates,
I and previously reported Cu(I) η2-arene complex, 6.19e Mid-
dle: DFT computational model, I* (B3LYP-D3BJ/6-311+G(p,d).
Bottom: HOMO-10 (left) and HOMO-9 (right), hydrogens
omitted for clarity, isovalue = 0.05 (electron/bohr3)1/2
.
The calculated Cu-C distances of 2.15 and 2.25 Å
are comparable with the bond metrics associated with
previously reported, structurally characterized Cu(I)
arene complexes, 6.19e The DFT analysis suggests that the
bonding interaction between the η2-arene function and
the copper center has both σ and π-symmetry compo-
nents. Interestingly, Fukuzumi and Itoh showed that both
the redox potential and the rate of oxidation of the com-
plexes 6 is strongly dependent on the electronic proper-
ties of the substituted arene, with more facile oxidation
occurring with inductive substituents.19e In the reaction of
6 with oxygen, the oxidation rate increases with decreas-
ing Cu-arene stability, which is in turn associated with a
less electron-rich arene, suggesting that formation of the
bridging peroxo LCu-O2-CuL occurs after arene dissocia-
tion.19e In contrast, our data indicate an increased rate of
reaction with more electron-rich arenes suggesting that
the oxidation of the copper occurs prior to arene decoor-
dination, consistent with Fukuzumi and Itoh’s electro-
chemical oxidations.19e With regards to the subsequent C-
H activation step, this may well occur by a radical path-
way as evidenced by the suppression of cyclization of 3a
in the presence of two equivalents of TEMPO and the
recovery of >95% of the starting material.
Conclusion
In summary we have developed the copper-catalyzed syn-
thesis of isoindolinones via a tolylsulfonamide- or nosyl-
sulfonamide-directed C-H functionalization, a process in
which the sulfonamide acts as both the directing group
and the functionalizing reagent. Subsequent samarium-
mediated removal of the sulfonyl function leads to the
free isoindolinone. The substrate scope of the reaction
and the results from preliminary mechanistic and compu-
tational studies point to the possible involvement of arene
π-coordination in the rate-determining step of the reac-
tion, which may well be oxidation of the copper center.
We are currently probing this putative mechanism more
deeply with a view to exploiting it in novel catalytic pro-
cesses, and the results of these studies will be presented
in due course.
Experimental Section
General Experimental Information. Reagents were
used as supplied from commercial sources. Anhydrous
THF was obtained from a purification column composed
of activated alumina and subsequently stored under ni-
trogen. All other anhydrous solvents were prepared by
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drying the corresponding reagent grade solvent over mo-
145.31, 160.2, 162.6, 166.3; 19F NMR (377 MHz, CDCl3) δ -
116.8; IR (neat, cm-1): 3248, 3102, 2856, 1677, 1597, 1575,
1506, 1412, 1345, 1220, 1188, 1165, 1062; HRMS (ESI): calcd
for C21H19 FNO3S [(M+H)+]: 384.1064, found 384.1068.
1
2
3
lecular sieves. Mass Spectrometry was carried out with a
MicrOTOF II spectrometer (Electrospray (ESI), with a
time-of-flight (TOF) analyzer type.
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2-(4-(tert-Butyl)benzyl)-N-tosylbenzamide, (3e). White
solid (1.12 g, 89%), m.p. 150 – 151 °C; H NMR (400 MHz,
General Procedure for the Preparation of Substrates,
3. Following a reported procedure,20 p-toluenesulfonyl
isocyanate (592 mg, 3 mmol) was added to a solution of
the appropriate 2-benzylbenzoic acid (1 eq) in THF (0.5 M
solution) and stirred at room temperature for 10 minutes.
Triethylamine (306 mg, 3 mmol) was added dropwise to
the solution with evolution of gas and the reaction pro-
gress was monitored using an oil bubbler. Upon comple-
tion of the reaction (typically 3 h) ethyl acetate and aque-
ous HCl (2M) were added to the mixture. The organic
phase was washed with brine and dried over MgSO4. The
volatiles were removed under reduced pressure and the
resulting solid was purified by recrystallisation from ethyl
acetate: petroleum ether (60/80) (1:4) to give the pure
product.
1
CDCl3) δ 1.28 (s, 9H), 2.47 (s, 3H), 4.03 (s, 2H), 6.91 (d, J =
8.1 Hz, 2H), 7.15 – 7.25 (m, 4H), 7.32 – 7.46 (m, 4H), 7.99
(d, J = 8.2 Hz, 2H), 8.45 (s, 1H); 13C NMR (101 MHz, CDCl3)
δ 21.8, 31.5, 34.4, 37.9, 125.6, 126.6, 127.8, 128.5, 128.7, 129.7,
131.5, 131.9, 132.6, 135.7, 137.1, 140.9, 145.2, 149.2, 166.5;
IR (neat, cm-1): 3258, 2960, 1702, 1594, 1513, 1409, 1345, 1162,
1042, 660; HRMS (ESI): calcd for C25H28NO3S [(M+H)+]:
422.1784, found 422.1792.
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2-(4-chlorobenzyl)-N-tosylbenzamide (3f). White solid
(0.63 g, 52%), m.p. 111 – 112 °C; 1H NMR (400 MHz, CDCl3)
δ 2.47 (s, 3H), 4.04 (s, 2H), 6.80 – 6.86 (m, 2H), 6.99 –
7.05 (m, 2H), 7.19 (d, J = 7.7 Hz, 1H), 7.22 – 7.29 (m, 1H),
7.33 (d, J = 8.1 Hz, 2H), 7.36 – 7.43 (m, 1H), 7.45 (dd, J =
7.6, 1.4 Hz, 1H), 7.87 – 7.93 (m, 2H), 8.44 – 8.54 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 21.9, 37.9, 127.0, 127.9, 128.5,
128.6, 129.7, 130.2, 131.8, 132.0, 132.2, 132.4, 135.5, 138.7,
140.6, 145.3, 166.2; IR (neat, cm-1): 3068, 2868, 1672, 1597,
1573, 1436, 1357, 1254, 1169, 1088, 1069; HRMS (ESI): calcd
for C21H19ClNO3S [(M+H)+]: 400.0769, found 400.0779.
2-Benzyl-N-tosylbenzamide (3a). White solid (0.90 g,
82%).The spectroscopic data are in agreement with litera-
1
ture 21, m.p. 156-157 °C; H NMR (400 MHz, CDCl3) δ 2.44
(s, 3H), 4.05 (s, 2H), 6.90 – 6.99 (m, 2H), 7.08 – 7.27 (m,
5H), 7.27 – 7.46 (m, 4H), 7.93 (d, J = 8.0 Hz, 2H), 8.44 (s,
1H, NH); 13C NMR (101 MHz, CDCl3) δ 21.8, 38.4, 126.2,
126.6, 127.7, 128.5, 128.6, 128.8, 129.6, 131.6, 131.9, 132.5, 135.5,
140.1, 140.6, 145.1, 166.3; IR: 3066, 2862, 1672, 1575, 1594,
1493, 1440, 1351, 1255; IR (neat, cm-1): 3065, 2861, 1672, 1594,
1574, 1493, 1439, 1351, 1255, 1167; 1075.72; HRMS (ESI): calcd
for C21H20NO3S [(M+H)+]: 366.1158, found 366.1164.
2-Benzyl-4-methyl-N-tosylbenzamide (3g). White solid
1
(0.83 g, 73%), m.p. 126 – 127 °C; H NMR (400 MHz,
CDCl3) δ 2.28 (s, 3H), 2.45 (s, 3H), 4.04 (s, 2H), 6.93 – 7.01
(m, 2H), 7.07 (d, J = 7.8 Hz, 1H), 7.16 (m, 4H), 7.28 – 7.35
(m, 3H), 7.95 (m, 2H), 8.97 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 20.7, 21.7, 37.9, 126.0, 128.4, 128.4, 128.47, 128.7,
129.6, 131.4, 132.1, 132.6, 135.5, 136.3, 137.6, 140.4, 145.0, 166.7;
IR (neat, cm-1): 3188, 2920, 1695, 1672, 1595, 1490, 1429,
1341, 1294, 1167, 1062; HRMS (ESI): calcd for C22H22NO3S
[(M+H)+]: 380.1315, found 380.1312.
2-(4-Methylbenzyl)-N-tosylbenzamide (3b). White
1
solid (0.95 g, 83%), m.p. 116 – 117 °C; H NMR (400 MHz,
CDCl3) δ 2.28 (s, 3H), 2.46 (s, 3H), 4.02 (s, 2H), 6.85 (d, J =
7.8 Hz, 2H), 6.96 (d, J = 7.7 Hz, 2H), 7.18 – 7.25 (m, 2H),
7.30 – 7.46 (m, 4H), 7.96 (d, J = 8.2 Hz, 2H), 8.51 (s, 1H);
13C NMR (101 MHz, CDCl3) δ 21.0, 21.7, 37.9, 126.4, 127.7,
128.5, 128.6, 129.2, 129.5, 131.4, 131.8, 132.4, 135.4, 135.6, 136.9,
140.7, 145.0, 166.3; IR (neat, cm-1): 3350, 3258, 1669, 1597,
1488, 1305, 1153, 1093, 900; HRMS (ESI): calcd for
C22H22NO3S [(M+H)+]: 380.1315, found 380.1316.
2-Benzyl-4-methoxy-N-tosylbenzamide (3h). White solid
1
(0.78 g, 66%), m.p. 147 – 148 °C; H NMR (400 MHz,
CDCl3) δ 2.45 (s, 3H), 3.74 (s, 3H), 4.10 (s, 2H), 6.66 – 6.73
(m, 2H), 6.93 – 7.00 (m, 2H), 7.09 – 7.18 (m, 3H), 7.31 (d, J
= 8.1 Hz, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.4 Hz,
2H), 8.71 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 21.8, 38.7,
55.4, 111.1, 117.6, 124.2, 126.2, 128.5, 128.53, 128.9, 129.6, 130.3,
135.7, 140.1, 143.9, 144.9, 162.3, 166.0; IR (neat, cm-1): 3208,
3028, 2927, 2857, 1692, 1594, 1492, 1449, 1422, 1345, 1235,
1171; HRMS (ESI): calcd for C22H22NO4S [(M+H)+]:
396.1264, found 396.1263.
2-(4-Methoxybenzyl)-N-tosylbenzamide (3c). White solid
(1.07 g, 91%), m.p. 136 – 137 °C; 1H NMR (400 MHz, CDCl3)
δ 2.47 (s, 3H), 3.76 (s, 3H), 4.01 (s, 2H), 6.66 – 6.72 (m,
2H), 6.85 – 6.91 (m, 2H), 7.20 – 7.24 (m, 1H), 7.26 (s, 1H),
7.29 – 7.45 (m, 4H), 7.95 – 8.00 (m, 2H), 8.11 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 21.8, 37.6, 55.3, 114.0, 126.6, 127.8,
128.6, 129.6, 129.8, 131.5, 131.9, 132.2, 132.5, 135.6, 141.1, 145.2,
158.0, 166.4; IR (neat, cm-1): 3354, 3259, 3067, 2836, 1665,
1597, 1573, 1508, 1443, 1355, 1242, 1170; HRMS (ESI): calcd
for C22H22NO4S [(M+H)+]: 396.1264, found 396.1257.
2-Benzyl-4-fluoro-N-tosylbenzamide (3i). White solid (0.85
1
g, 74%), m.p. 137 – 138 °C; H NMR (400 MHz, CDCl3) δ
2.45 (s, 3H), 4.05 (s, 2H), 6.81 – 6.93 (m, 2H), 6.93 – 7.01
(m, 2H), 7.12 – 7.21 (m, 3H), 7.32 (d, J = 8.1 Hz, 2H), 7.44 –
7.51 (m, 1H), 7.89 – 7.97 (m, 2H), 8.80 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 21.7, 38.3, 113.5 (d, J = 21.8 Hz), 118.3 (d, J =
22.0 Hz), 126.5, 128.4 (d, J = 3.2 Hz), 128.5, 128.6, 128.8,
129.6, 130.2 (d, J = 9.3 Hz), 135.3, 139.2, 144.5 (d, J = 8.1 Hz),
145.2 , 163.1, 165.6; 19F NMR (283 MHz, CDCl3) δ -106.2;
IR (neat, cm-1): 3105, 1674, 1597, 1581, 1454, 1439, 1358, 1237,
1175; HRMS (ESI): calcd for C21H19FNO3S [(M+H)+]:
384.1064, found 384.1058.
2-(4-Fluorobenzyl)-N-tosylbenzamide (3d). White solid
1
(0.96 g, 84%), m.p. 119 – 120 °C; H NMR (400 MHz,
CDCl3) δ 2.47 (s, 3H), 4.05 (s, 2H), 6.72 – 6.81 (m, 2H),
6.85 – 6.92 (m, 2H), 7.16 – 7.25 (m, 2H), 7.33 (m, 2H), 7.38
(m, 1H), 7.46 (m, 1H), 7.87 – 7.96 (m, 2H), 8.75 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 21.8, 37.8, 115.2 (d, J = 21.3 Hz,
CHCF), 126.8, 127.9, 128.6, 129.7, 130.2 (d, J = 7.8 Hz,
CHCHCF), 131.6, 132.1, 135.5, 135.9 (d, J = 3.1 Hz, CF), 140.8,
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2-(1-Phenylethyl)-N-tosylbenzamide (3j). White solid (0.69
(193 mg, 0.6 mmol) were added to a Young’s tube under
g, 61%), m.p. 132 – 133 °C; 1H NMR (400 MHz, CDCl3) δ
1.51 (d, J = 7.2 Hz, 3H), 2.46 (s, 3H), 4.56 (q, J = 7.2 Hz, 1H),
6.97 – 7.05 (m, 2H), 7.08 – 7.23 (m, 4H), 7.28 – 7.44 (m,
atmospheric conditions. Chlorobenzene (5 ml) and acetic
acid (1 ml) were added sequentially and the tube was
sealed with a PTFE tap. The reaction vessel was heated to
120 °C and stirred at this temperature for 16 hrs. After
cooling to room temperature the volatiles were removed
under reduced pressure and the crude product was sub-
jected to column chromatography using an EtOAc: petro-
leum ether (40-60 °C) 1:3 mix as eluent to yield the pure
product.
1
2
3
4
5
6
7
8
13
5H), 7.92 – 8.00 (m, 2H), 8.33 (s, 1H); C NMR (101 MHz,
CDCl3) δ 21.9, 22.0, 39.8, 126.3, 126.3, 127.3, 127.7, 128.4,
128.5, 128.7, 129.7, 131.8, 132.9, 135.6, 145.3, 145.3, 145.5,
166.8; IR (neat, cm-1): 3223, 3020, 2981, 1710, 1596, 1574,
1403, 1341, 1230, 1164; HRMS (ESI): calcd for C22H22NO3S
[(M+H)+]: 380.1315, found 380.1295.
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60
(1R,2S)-2-Benzyl-N-tosylcyclohexanecarboxamide
(3k).
3-Phenyl-2-tosylisoindolin-1-one (4a). White solid
(66 mg, 61%). The spectroscopic data are in agreement
with the literature 23, m.p. 173 – 174 °C; 1H NMR (400 MHz,
CDCl3) δ 2.36 (s, 3H), 6.22 (s, 1H), 7.05 – 7.10 (m, 2H), 7.10
– 7.18 (m, 3H), 7.22 – 7.35 (m, 3H), 7.43 – 7.59 (m, 4H),
White solid (0.89 g, 80%), m.p. 107 – 108 °C; 1H NMR (400
MHz, CDCl3) δ 0.82 (q, J = 11.5, 10.9 Hz, 1H), 0.94 – 1.23 (m,
2H), 1.31 – 1.45 (m, 1H), 1.50 – 1.65 (m, 2H), 1.64 – 1.90 (m,
3H), 1.90 – 2.14 (m, 2H), 2.39 (s, 3H), 2.50 (dd, J = 13.1, 2.6
Hz, 1H), 6.88 – 7.00 (m, 2H), 7.11 – 7.23 (m, 3H), 7.28 – 7.35
(m, 2H), 8.00 (d, J = 8.3 Hz, 2H), 8.98 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 21.8, 25.3, 25.4, 30.1, 30.2, 40.8 (2C), 51.7,
126.0, 128.2, 128.5, 129.4, 129.8, 135.7, 139.7, 145.3, 174.1;
IR (neat, cm-1): 3185, 2933, 2857, 1677, 1597, 1493, 1448, 1353,
1173, 1133, 1086; HRMS (ESI): calcd for C21H26NO3S
[(M+H)+]: 372.1628, found 372.1624.
13
7.86 (d, J = 7.6 Hz, 1H); C NMR (101 MHz, CDCl3) δ 21.8,
65.8, 123.9, 124.9, 128.2, 128.3, 128.8, 128.9, 129.0, 129.1,
129.3, 134.5, 136.1, 137.1, 144.8, 146.6, 166.6; IR (neat, cm-1):
3066, 1722, 1597, 1493, 1458, 1365, 1285, 1168; HRMS (ESI):
calcd for C21H18NO3S [(M+H)+]: 364.1002, found 364.1002.
3-(p-Tolyl)-2-tosylisoindolin-1-one (4b). White
solid (86 mg, 74%), m.p. 185 – 186 °C; 1H NMR (400 MHz,
CDCl3) δ 2.34 (s, 3H), 2.36 (s, 3H), 6.19 (s, 1H), 6.94 – 7.00
(m, 2H), 7.04 – 7.09 (m, 2H), 7.11 – 7.18 (m, 4H), 7.42 –
7.48 (m, 1H), 7.51 – 7.57 (m, 3H), 7.84 (dd, J = 7.6, 0.8 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 21.1, 21.6, 65.4, 123.6,
124.6, 127.9, 128.1, 128.8, 128.8, 129.1, 129.3, 133.9, 134.2,
135.9, 138.5, 144.6, 146.5, 166.4; IR (neat, cm-1): 1730, 1610,
1595, 1468, 1351, 1286, 1168, 1099, 1019; HRMS (ESI): calcd
for C22H20NO3S [(M+H)+]: 378.1158, found 378.1159.
Procedure for the synthesis of 2-(4-Methylbenzyl)-N-
nosylbenzamide (3l). Following a reported procedure,22
to a suspension of EDCl·HCl (0.11 g, 0.52 mmol) in CH2Cl2
(5ml) was added DMAP (0.12 g, 1.05 mmol) and the mix-
ture was stirred at room temperature for 15 min or until
the solids dissolved. Then, the reaction was cooled to 0°C
and was added 2-(4-methylbenzyl)benzoic acid (0.1 g,
0.44 mmol) followed by p-nitrobenzenesulfonamide (0.12
g, 0.59 mmol) and the mixture was stirred for 24 h at
room temperature. Diethyl ether was added and the or-
ganic mixture was washed with aqueous HCl (2M). The
aqueous layer was extracted with EtOAc and the organic
layers was pooled, washed with brine, dried over Na2SO4.
The volatiles were removed under reduced pressure and
the resulting solid was purified by column chromatog-
raphy using an EtOAc: hexane (5:5) mix as eluent to yield
the pure product. White solid (0.14 g, 79%), m.p. 167-168
3-(4-Methoxyphenyl)-2-tosylisoindolin-1-one (4c).
1
White solid (84 mg, 71%), m.p. 161 – 162 °C; H NMR (400
MHz, CDCl3) δ 2.35 (s, 3H), 3.80 (s, 3H), 6.19 (s, 1H), 6.74 –
6.80 (m, 2H), 6.95 – 7.02 (m, 2H), 7.11 – 7.19 (m, 3H), 7.42
– 7.49 (m, 1H), 7.49 – 7.59 (m, 3H), 7.84 (dd, J = 7.6, 1.0
13
Hz, 1H); C NMR (101 MHz, CDCl3) δ 21.7, 55.5, 65.4, 114.1,
123.8, 124.7, 128.2, 128.9, 129.0, 129.0, 129.3, 129.6, 134.4,
136.2, 144.7, 146.8, 160.0, 166.5; IR (neat, cm-1): 2928, 2836,
1728, 1608, 1597, 1510, 1466, 1348, 1248, 1167, 1084; HRMS
(ESI): calcd for C22H19NO4S [(M+H)+]: 394.1108, found
394.1118.
1
°C; H NMR (500 MHz, (CD3)2CO) δ 2.20 (s, 3H), 4.04 (s,
2H), 6.77 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 7.32 –
7.27 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz,
1H), 8.26 (d, J = 9.3 Hz, 2H), 8.40 (d, J = 7.9 Hz, 2H); 13C
NMR (500 MHz, (CD3)2CO) δ 19.9, 37.3, 124.0, 126.1, 127.1,
128.3, 128.5, 128.7, 128.7, 128.9, 129.5, 130.4, 131.2, 131.4, 135.0,
137.5, 140.7; IR (neat, cm-1): 3106, 2924, 1684, 1526, 1426,
1351, 1243, 1181, 1059; HRMS (ESI): calcd for C21H18N2O5S
[(M+Na)+]: 433.0828, found 433.0832.
3-(4-fluorophenyl)-2-tosylisoindolin-1-one, (4d).
White solid (84 mg, 74%), m.p. 141 – 142 °C; 1H NMR (400
MHz, CDCl3) δ 2.37 (s, 3H), 6.21 (s, 1H), 6.91 – 6.99 (m,
2H), 7.04 – 7.10 (m, 2H), 7.12 – 7.19 (m, 3H), 7.44 – 7.60
13
(m, 4H), 7.82 – 7.91 (m, 1H); C NMR (101 MHz, CDCl3) δ
21.8, 65.0, 115.8 (d, J = 22.4 Hz), 123.8, 125.0, 128.2, 129.0,
129.3, 129.4, 130.0 (d, J = 8.8 Hz), 133.0, 134.6, 136.1, 145.0,
146.3, 162.9 (d, J = 248 Hz), 166.4; 19F NMR (377 MHz,
CDCl3) δ -112.5; IR (neat, cm-1): 2922, 2853, 1760, 1719, 1679,
1508, 1287, 1226, 1185, 1168; HRMS (ESI): calcd for
C21H16FNO3S [(M+H)+]: 382.0908, found 382.0910.
Sulfamidation Optimization Study (Table 1).
The optimization study was performed according to gen-
eral procedure given below, varied according to the en-
tries in Table 1. The product, 4a, was not isolated, rather
the spectroscopic yield of 4a was determined by H NMR
spectroscopy, using an internal standard (1,3,5-
trimethoxybenzene).
1
3-(4-(tert-butyl)phenyl)-2-tosylisoindolin-1-one,
(4e). White solid (89 mg, 71%), m.p. 230 – 231 °C; 1H NMR
(400 MHz, CDCl3) δ 1.31 (s, 9H), 2.34 (s, 3H), 6.20 (s, 1H),
6.93 – 6.98 (m, 2H), 7.05 – 7.10 (m, 2H), 7.16 – 7.21 (m, 1H),
7.21 – 7.25 (m, 2H), 7.41 – 7.49 (m, 3H), 7.53 – 7.58 (m, 1H),
General Procedure for the Synthesis of Iso-
indolinones, 4 (Table 1). The appropriate substrate 3
(0.3 mmol), Cu(OTf)2 (22 mg, 0.06 mmol) and PhI(OAc)2
13
7.87 (d, J = 7.7 Hz, 1H); C NMR (101 MHz, CDCl3) δ 21.7,
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(3aR,7aR)-3-Phenyl-2-tosyloctahydro-1H-isoindol-
31.4, 34.7, 65.5, 123.9, 124.7, 125.6, 128.0, 128.1, 129.0, 129.1,
1-one (4k). White solid (52 mg, 47%), m.p. 173 – 174 °C; 1H
NMR (400 MHz, CDCl3) δ 1.15 – 1.28 (m, 4H), 1.53 – 1.86
(m, 4H), 1.96 – 2.19 (m, 2H), 2.41 (s, 3H), 4.72 (d, J = 9.9
Hz, 1H), 7.15 (d, J = 2.3 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H),
7.27 – 7.33 (m, 3H), 7.57 – 7.63 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 21.8, 25.2, 25.3, 25.4, 27.5, 48.5, 49.6, 69.8,
127.3, 128.3, 128.6, 129.2, 129.3, 136.6, 138.7, 144.6, 175.0;
IR (neat, cm-1):2928, 2857, 1736, 1594, 1493, 1454, 1357, 1159,
1106; HRMS (ESI): calcd for C21H24NO3S [(M+H)+]: 370.1471,
found 370.1467.
1
2
3
4
5
6
7
8
129.2, 133.7, 134.4, 136.2, 144.6, 146.6, 151.9, 166.5; IR (neat,
cm-1): 3668, 2965, 2928, 2863, 1736, 1718, 1594, 1493, 1554,
1358, 1168, 1106, 1085; HRMS (ESI): calcd for C25H26NO3S
[(M+H)+]: 420.1628, found 420.1625.
3-(4-chlorophenyl)-2-tosylisoindolin-1-one,
(4f).
1
White solid (86 mg, 72%), m.p. 83 – 84 °C; H NMR (400
MHz, CDCl3) δ 2.38 (s, 3H), 6.18 (s, 1H), 7.00 – 7.06 (m,
2H), 7.11 – 7.20 (m, 3H), 7.21 – 7.26 (m, 2H), 7.45 – 7.51 (m,
1H), 7.54 – 7.60 (m, 3H), 7.83 – 7.88 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 21.8, 64.9, 123.8, 125.0, 128.2, 128.9, 129.1,
129.4, 129.4, 129.5, 134.6, 134.8, 135.7, 136.0, 145.1, 146.0,
166.4; IR (neat, cm-1): 3092, 2922, 2853, 1734, 1610, 1594,
1491, 1468, 1359, 1288, 1169, 1087; HRMS (ESI): calcd for
C21H17ClNO3S [(M+H)+]: 398.0612, found 398.0622.
9
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59
60
3-(p-Tolyl)-2-nosylisoindolin-1-one (4l). White
1
solid (96 mg, 78%), m.p. 201-202 °C; H NMR (500 MHz,
CDCl3) δ; 2.36 (s, 3H), 6.23 (s, 1H), 6.91 (d, J = 8.3 Hz, 2H),
7.06 (d, J = 7.6 Hz, 2H), 7.19 (dd, J = 7.6, 0.7 Hz, 1H), 7.52
(t, J = 7.5 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.77 (d, J = 9.1
Hz, 2H), 7.90 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 9.1 Hz, 2H); 13C
NMR (500 MHz, CDCl3) δ 21.1, 65.6, 123.6, 123.8, 124.8,
128.2, 128.3, 129.2, 129.2, 129.4, 133.1, 134.8, 139.2, 144.3,
146.3, 150.3, 166.2; IR (neat, cm-1): 2928, 2857, 1722, 1528,
1384, 1348, 1285, 1176, 1102, 855; HRMS (ESI): calcd for
C21H16N2O5S [(M+Na)+]: 431.067213, found 431.066711.
5-methyl-3-phenyl-2-tosylisoindolin-1-one
(4g).
White solid (83 mg, 73%), m.p. 184 – 185 °C; 1H NMR (400
MHz, CDCl3) δ 2.36 (s, 3H), 2.41 (s, 3H), 6.17 (s, 1H), 7.01 –
7.10 (m, 3H), 7.13 (d, J = 8.3 Hz, 2H), 7.22 – 7.26 (m, 2H),
7.28 – 7.39 (m, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 21.4, 21.7, 65.6, 123.6, 124.8, 128.2,
128.2, 128.7, 128.8, 129.1, 129.3, 135.6, 136.2, 137.3, 139.4,
144.0, 144.8, 166.7; IR (neat, cm-1): 2917, 1720, 1594, 1493,
1362, 1185, 1079; HRMS (ESI): calcd for C22H20NO3S
[(M+H)+]: 378.1158, found 378.1162.
Procedure for the Deprotection of N-Sulfonyl
Isoindolinones. Following a reported procedure,13 to a
solution of SmI2 (26.4 ml, 0.1 M, 2.64 mmol) in THF was
added the protected isoindolinone (4b or 4l) (0.264
mmol), water (142 µL, 7.92 mmol) and pyrrolidine (0.44
ml, 5.28 mmol) under a nitrogen atmosphere. The mix-
ture of reaction was diluted with diethyl ether (20 ml) and
a solution of potassium sodium tartrate and potassium
carbonate (10% w/v each) was added. The aqueous phase
was extracted with diethyl ether and the organic extract
was dried over Na2SO4. The volatiles were removed under
reduced pressure and the resulting crude product was
dissolved in DCM and purified by ion exchange column
(propylsulfonic acid functionalized silica) to yield the
pure product. White solid (36 mg, 62%, from 4b) and (42
mg, 71 %, from 4l). The spectroscopic data are in agree-
5-Methoxy-3-phenyl-2-tosylisoindolin-1-one (4h).
1
White solid (83 mg, 73%), m.p. 208 – 209 °C; H NMR
(400 MHz, CDCl3) δ 2.35 (s, 3H), 3.76 (s, 3H), 6.14 (s, 1H),
6.56 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.5, 2.1 Hz, 1H), 7.05 –
7.16 (m, 4H), 7.22 – 7.36 (m, 3H), 7.47 – 7.52 (m, 2H), 7.76
(d, J = 8.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 21.7, 55.9,
65.4, 107.7, 116.6, 121.4, 126.5, 128.2, 128.2, 128.8, 128.9, 129.3,
136.3, 137.3, 144.7, 149.1, 165.0, 166.2; IR (neat, cm-1): 2942,
1727, 1605, 1490, 1359, 1295, 1244, 1169, 1094, 1080; HRMS
(ESI): calcd for C22H20NO4S [(M+H)+]: 394.1108, found
394.1120.
5-Fluoro-3-phenyl-2-tosylisoindolin-1-one
(4i).
1
White solid (55 mg, 47%), m.p. 170 – 171 °C; H NMR (400
MHz, Cdcl3) δ 2.36 (s, 3H), 6.18 (s, 1H), 6.80 – 6.87 (m,
1H), 7.04 – 7.09 (m, 2H), 7.10 – 7.19 (m, 3H), 7.24 – 7.31 (m,
2H), 7.31 – 7.37 (m, 1H), 7.47 – 7.52 (m, 2H), 7.82 – 7.90
(m, 1H); 13C NMR (101 MHz, CDCl3) δ 21.7, 65.2, 111.1 (d, J =
24.6 Hz), 117.4 (d, J = 24.0 Hz), 125.1, 127.2 (d, J = 10.0 Hz),
128.1, 128.2, 129.0, 129.0, 129.3, 135.9, 136.4, 144.9, 149.0 (d, J
= 10.2 Hz), 165.3 (d, J = 255.5 Hz), 168.0; 19F NMR (377
MHz, CDCl3) δ -101.7; IR (neat, cm-1): 3069, 2920, 1718,
1618, 1600, 1483, 1367, 1304, 1261, 1239, 1169; HRMS (ESI):
calcd for C21H17FNO3S [(M+H)+]: 382.0908, found 382.0903.
1
ment with the literature,24 m.p. 179-181 °C; H NMR (400
MHz, DMSO) δ 2.29 (s, 3H), 5.69 (s, 1H), 7.18 (s, 4H), 7.29
(dd, J = 0.9, 7.3 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.56 (td, J =
1.3, 7.3 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 9.02 (s, 1H); 13C
NMR (400 MHz, CDCl3) δ 21.2, 60.7, 123.4, 123.9, 126.8,
128.4, 129.8, 131.7, 132.4, 135.4, 138.5, 148.2, 171.0; IR (neat,
cm-1): 3183, 3063, 2859, 1681, 1607, 1510, 1465, 1357, 1299,
1264, 1139, 1022, 951, 849; HRMS (ESI): calcd for
C15H13NO[(M+Na)+]: 246.0889, found 246.0900.
3-methyl-3-phenyl-2-tosylisoindolin-1-one
(4j).
ASSOCIATED CONTENT
Supporting Information
1
White solid (52 mg, 46%), m.p. 71 – 72 °C; H NMR (400
MHz, CDCl3) δ 2.37 (s, 3H), 2.40 (s, 3H), 7.05 – 7.10 (m,
1H), 7.13 – 7.22 (m, 4H), 7.22 – 7.34 (m, 3H), 7.39 – 7.47 (m,
The Supporting Information is available free of charge on the
ACS Publications website.
13
1H), 7.50 – 7.59 (m, 3H), 7.83 (d, J = 7.6 Hz, 1H); C NMR
(101 MHz, CDCl3) δ 21.7, 25.4, 71.7, 122.4, 124.7, 127.1, 127.5,
128.2, 128.6, 128.8, 128.8, 129.1, 134.7, 136.4, 139.7, 144.8,
153.2, 166.8; IR (neat, cm-1):2921, 2851, 1725, 1611, 1597, 1494,
1466, 1448, 1357, 1289, 1260, 1167; HRMS (ESI): calcd for
C22H20NO3S [(M+H)+]: 378.1158, found 378.1157.
Details of deuterium-labeling experiments, copies of NMR
spectra, computation methods and data (PDF)
AUTHOR INFORMATION
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Page 8 of 9
(10) K. Nozawa-Kumada, J. Kadokawa, T. Kameyama and Y.
Corresponding Author
1
2
3
KondoꢀOrg. Lett. 2015, 17, 4479.
* r.bedford@bristol.ac.uk.
(11) Verma, A.; Patel, S.; Meenakshi; Kumar, A.; Yadav, A.;
Kumar, S.; Jana, S.; Sharma, S.; Prasad, Ch. D.; Kumar, S. Chem.
Commun. 2015, 51, 1371.
Author Contributions
4
5
6
7
8
9
(12) No activity was observed in the absence of Cu(OTf)2 or on
using rhodium(II) or palladium(II) acetate in place of Cu(OTf)2.
(13) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503.
(14) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(15) Note: The p-Cl and p-F-containing substrates gave the
same and faster rates than the unsubstituted analogue respec-
tively. This may indicate a change in either the mechanism or
the rate-determining step in the reaction of the substrates with
electron-withdrawing groups. Ignoring these two substrates
leads to an improved correlation with σ+ and σ with R2 values of
0.91 and 0.64 respectively.
All authors have given approval to the final version of the
manuscript.
ACKNOWLEDGMENT
We gratefully thank the EPSRC for the provision of a stu-
dentship (JGB) and CONICYT for the provision of a Becas
Chile postdoctoral fellowship (C.M.G.).
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