Design and synthesis of chiral urea-derived iodoarenes and their assessment in the enantioselective dearomatizing cyclization of a naphthyl amide

Article abstract of DOI:10.1016/j.tet.2020.131634

A novel family of urea-derived chiral iodoarenes was designed and synthesized for use in enantioselective iodine(I/III) catalysis. Their preparation required the development of a bidirectional synthetic strategy. These new chiral iodoarenes were assessed as catalysts in the dearomatizing cyclization of a naphthyl amide and provided moderate yields of product in some cases with low enantioselectivities.

Full text of DOI:10.1016/j.tet.2020.131634

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Design and synthesis of chiral urea-derived iodoarenes and their assessment in the
enantioselective dearomatizing cyclization of a naphthyl amide
M. Umair Tariq, Wesley J. Moran
PII:
S0040-4020(20)30841-3
https://doi.org/10.1016/j.tet.2020.131634
TET 131634
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 August 2020
Revised Date: 3 September 2020
Accepted Date: 14 September 2020
Please cite this article as: Tariq MU, Moran WJ, Design and synthesis of chiral urea-derived
iodoarenes and their assessment in the enantioselective dearomatizing cyclization of a naphthyl amide,
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Design and synthesis of chiral urea-derived
iodoarenes and their assessment in the
enantioselective dearomatizing cyclization of
a naphthyl amide
Leave this area blank for abstract info.
M. Umair Tariq and Wesley J. Moran
Department of Chemistry, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, U.K.

1
Tetrahedron
journal homepage: www.elsevier.com
Design and synthesis of chiral urea-derived iodoarenes and their assessment in the
enantioselective dearomatizing cyclization of a naphthyl amide
a
a
M. Umair Tariq and Wesley J Moran ∗
a
Department of Chemistry, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, U.K.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel family of urea-derived chiral iodoarenes was designed and synthesized for use in
enantioselective iodine(I/III) catalysis. Their preparation required the development of a
bidirectional synthetic strategy. These new chiral iodoarenes were assessed as catalysts in the
dearomatizing cyclization of a naphthyl amide and provided moderate yields of product in some
cases with low enantioselectivities.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
catalysis
hypervalent iodine
iodoarene
dearomatization
cyclization
—
——
∗
Corresponding author. e-mail: w.j.moran@hud.ac.uk

2
Tetrahedron
1
. Introduction
suggested that the reaction could be rendered enantioselective but
that an alternative catalyst structure would probably be required
for high levels of enantioinduction.
Enantioselective reactions mediated or catalyzed by chiral
hypervalent iodine reagents or chiral iodoarene precatalysts have
1
attracted significant attention over the past decade. In this
regard, a variety of chiral iodoarene backbones have been
reported; however, the most successful, and most reported,
framework is the bislactate ethers 1 and 2 reported independently
2,3
by Fujita and Ishihara (Fig. 1). A number of modifications of
4
this skeleton have been investigated, as each new application
often requires a new derivative for optimal results. Other reported5
chiral iodoarenes include Zhang’s spirobiindane derivative 3,
6
7
Quideau’s helicene 4, Maruoka’s indane 5, Ibrahim’s
8
dimethanoanthracene 6,
derivative 7. More recently, Nachtsheim reported his second
generation triazole catalyst 8 which appears to yield superior
and Moran’s pseudoephedrine
9
10
selectivities in a range of enantioselective oxidation reactions. It
is clear that, as in other areas of enantioselective catalysis, there
is no panacea and the investigation of new chiral iodoarenes and
hypervalent iodine reagents is still of interest and importance.
Scheme 2. Initial attempts at the dearomatizing cyclization of
naphthyl amide 11a
At this juncture we wished to design a new family of chiral
iodoarenes for use in iodine(I/III) catalysis and investigate their
efficacy in the enantioselective dearomatizing cyclization of
naphthols. Specifically, we aimed to prepare novel iodoarenes
that could potentially form helical structures in solution in a
1
3
similar manner to lactates 1 and 2, as shown by Muñiz. It is
1
4,15
known that oligomeric ureas can adopt helical conformations,
therefore we designed a small family of iodoarenes containing
16
urea appendages (Fig. 2). It was anticipated that ureas 13 would
be readily prepared from the isocyanate 14, itself derived from 2-
iodoaniline 15. In a similar manner, the C symmetric bisureas 16
2
would be obtained from isocyanates 18, which could be prepared
from bisanilines 18 or dicarboxylic acids 19. We knew that these
ureas would not display helicity, as a chain of at least four ureas
would be required, but this was our starting point.
Fig. 1. Examples of chiral iodoarenes
We recently reported the dearomatizing cyclization of phenols
and naphthols with pendent amides catalyzed by iodoarenes
I
I
I
H
H
N
N
R'
NCO
NH2
11
(Scheme 1). We envisaged that the use of chiral iodoarene
O
R
I
precatalysts would enable the enantioselective cyclization of the
naphthols.
13
14
15
I
H
H
N
H
H
R'
N
N
N
R'
OCN
NCO
R
O
O
R
1
6
17
I
I
HO2C
CO2H
H2N
NH2
OR
1
9
18
Fig. 2. Retrosynthesis of novel chiral iodoarenes 13 and 16 containing
Scheme 1. Dearomatizing cyclization of phenols and
urea appendages
naphthols bearing pendent amides
In the event, 2-iodoaniline 15 was readily converted into
isocyanate 14, by the literature procedure, and this was
2
. Results and Discussion
17
efficiently transformed into ureas 13a and 13b in very good
yields under typical reaction conditions (Scheme 3).
At the outset of the project we tested the efficacy of the
known iodoarenes 1a and 2a on their ability to catalyze the
12
dearomatizing cyclization of naphthol 11a.
After some
experimentation with differentwe did weeyes solvents and
temperature, the best selectivity observed with 1a was 4% ee and
with 2a was 14% ee (Scheme 2). These preliminary observations

3
Scheme 3. Preparation of ureas 13a and 13b
Delighted by this success, we endeavored to prepare bisaniline
1
8 by an identical, but two-directional, two-step protocol starting
from commercially available 2,6-dinitroaniline 20 (Scheme 4).
Initial conversion of the amino group to an iodide through
18
diazotization proceeded to give 21 in good yield, however
subsequent attempts to reduce the two nitro groups were
unsuccessful. Treatment with Fe powder (under a variety of
conditions), H2 gas or hydrazine over Pd on charcoal, and
trichlorosilane were all ineffective. In all cases studied, partial
reductions and/or side reactions including deiodination were
observed.
Scheme 6. Preparation of bisureas 16
Scheme 4. Initial attempts to prepare bisaniline 18
Attempts to convert bisurea 16c into tetraurea 25 via
conversion of the primary alcohols into tosylates or primary
amines were unsuccessful (Scheme 7). In both cases, mixtures of
unknown compounds were formed. Similarly, attempts to convert
the carboxylic acids in 16f into amides via acid chloride
formation were unproductive. These ureas 16a-f exhibit low
solubility in organic solvents, which could explain the difficulties
faced in their synthetic manipulation.
Accordingly, we turned our attention to the second route
starting from 2-aminoisophthalic acid 22; this was converted
19
readily into iodide 19 in 80% yield (Scheme 5). Conversion of
the carboxylic acid directly to the isocyanate 17 using
diphenylphosphoroyl azide was unsuccessful; however,
successive conversion to the acid chloride and the azide 24 led to
the isocyanate 17 in quantitative yield by
a
Curtius
rearrangement.
Scheme 7. Unsuccessful attempts to prepare tetraurea 25
Next, we prepared alcohol 28, which contained a urea
functionality, and coupled this with bisisocyanate 17 (Scheme 8).
The desired product 29, which contained two urethanes and two
ureas, was isolated in good yield.
Scheme 5. Successful route to bisisocyanate 17
With the isocyanate 17 in hand, a variety of bisureas were
prepared by addition of amines in THF (Scheme 6). A range of
amino alcohols were used to generate ureas 16a-16e, which carry
primary or secondary alcohols apparently ready for further
derivatization. 16f has terminal carboxylic acid groups prone for
further functionalization. Finally, 16g is the benzoyl ester of 16c,
although it was prepared by the coupling reaction shown rather
than esterification.
Scheme 8. Preparation of mixed urethane-urea 29
The ability of these 10 novel urea-containing chiral iodoarenes
to effect the enantioselective dearomatizing cyclization of
naphthyl amide 11a was investigated (Table 1). A subset of the
experiments undertaken are presented but it can be seen that
products were typically obtained in low yields, and that they

4
Tetrahedron
could not be purified sufficiently for HPLC analysis. Using
3. Experimental section
iodoarene 16c did lead to pure samples of 12a being isolated,
however selectivity was very low (entries 7-9). Using polar
solvents like EtOH, MeOH and HFIP often leads to higher yields
of product but poorer levels of selectivity in hypervalent iodine
mediated reactions. The highest yield of product was obtained
with precatalyst 29, but the selectivity was just 2% ee. It is likely
that the active catalytic species, i.e. the iodine(III) compounds,
are even more sparingly soluble than the parent iodoarenes,
which could explain their low reactivities.
3
.1. General
9,20
Infrared (IR) spectra were recorded on a Nicolet 380,
equipped with a diamond probe ATR attachment. Low and high
resolution mass spectra (m/z) were obtained in the electrospray
(ESI) mode. Melting points (uncorrected) were measured on a
Stuart SMP10 apparatus. All reagents and solvents were used
without further purification except THF (dried over 3 Å MS and
Table 1. Efficacy of novel urea-based iodoarenes in the
dearomatizing cyclization of naphthyl amide 11a
then distilled over Na/benzophenone under N ). The reactions
2
were monitored by thin layer chromatography (TLC) using F254
pre-coated silica gel plates. Spots were visualized with UV,
KMnO4 stain or vanillin stain. Flash chromatography was
performed with 35-70 μm, 60 Å silica gel.
O
Ph
Ph
N
NH
OH
20 mol% precatalyst
O
*
O
1
.2 equiv m-CPBA, solvent
temperature, 16 h
3.2. Synthesis of 2'-phenyl-2H,4'H-spiro[naphthalene-1,5'-
oxazol]-2-one (12a)
11a
12a
o
a
c
Entry ArI
Solvent
T/ C
Yield %
<5
% ee
To a solution of amide 11a (1 equiv) in anhydrous solvent
0.030 M) at room temperature (or below) was added m-CPBA
2.2 equiv) and iodoarene catalyst (0.1 or 0.2 equiv). The reaction
mixture was stirred for 16 h and then quenched with a saturated
(
(
1
2
3
13a MeCN
13b MeCN
16a MeCN
20
-
-
-
20
<20
-20 (4 h), then
0
<30
solution of NaHCO . The organic layer was extracted with ethyl
3
2
acetate (three times), dried over MgSO4, filtered and
concentrated under vacuum. The resulting residue was purified
by flash chromatography (3:1 petroleum ether/EtOAc) to afford
4
5
16b MeCN
16b 3:1
-20 (4 h), then
0
<10
<10
<5
-
-
2
1
1
2a as a pale yellow oil. IR (thin film) 3160, 3053, 2869, 1715,
-78 (6 h), then
20
−1 1
673, 1652, 1603, 1569, 1547, 1367, 1338, 1283, 770 cm ; H
CH
2
Cl
2
/MeOH
NMR (CDCl , 400 MHz) 8.08-8.06 (m, 2H), 7.56-7.35 (m, 8H),
3
6
7
16c MeCN
16c 2:1
20
20
6
.21 (d, J = 10.0 Hz, 1H), 4.48 (d, J = 15.4 Hz, 1H), 4.01 (d, J =
b
13
68 (41)
1
15.4 Hz, 1H); C NMR (CDCl 100 MHz) 197.8, 164.3, 145.8,
3
MeCN/EtOH
1
42.3, 132.0, 131.0, 129.7, 129.0, 128.9, 128.8, 128.6, 127.0,
+
b
8
9
16c HFIP
40
25 (14)
4
3
125.7, 123.7, 86.6, 69.8; HRMS [M+H] m/z calc’d for
C H14NO requires 276.1019, found 276.1019. HPLC: Chiralpak
18 2
b
16c 3:1
-78 (6 h), then
20
(30)
IB, 254 nm, hexane/IPA gradient (100:0 to 90:10 over 35 min), 1
mL/min, retention times 12.9 & 15.1 minutes.
CH
2
Cl
2
/MeOH
/MeOH
1
0
16d MeCN
-20 (4 h), then
0
<10
-
2
3.3. Preparation of ureas 13
1
1
1
2
16e MeOH
16e 3:1
20
<5
<5
-
-
To the solution of 1-iodo-2-isocyanatobenzene 14 (0.50 g, 2.0
-78 (6 h), then
20
o
mmol, 1 equiv) in THF (30 mL) at 0 C was added a solution of
CH
MeCN
16g CH Cl
2 2
Cl
amino ester (2.2 mmol, 1.1 equiv) and triethylamine (0.57 mL,
.1 mmol, 2.0 equiv) in THF (10 mL) dropwise. Then, the ice
bath was removed and the reaction mixture was stirred overnight.
The reaction mixture was concentrated under reduced pressure
was washed with hexanes multiple times. Recrystallization either
with dichloromethane/ethyl acetate or ethanol provided the urea
1
1
3
4
16f
20
<5
-
-
4
2
2
-78 (6 h), then
0
<10
2
1
5
6
16g HFIP
29 MeCN
40
20
<36
-
b
1
56 (46)
2
1
3.
a
1
Yield determined by H NMR using 1,3,5-trimethoxybenzene as an internal
standard. Yield of pure isolated compound. Determined by chiral HPLC
analysis.
3
.3.1. Methyl ((2-iodophenyl)carbamoyl)-L-
leucinate (13a)
b
c
Yellow solid (0.58 g, 73%). M.p. 158-160 °C; IR 3301, 2951,
In summary, we have developed a synthetic route into urea-
based chiral iodoarenes. In particular, a two-directional strategy
to symmetrical bisureas has been revealed. Some of these
compounds can effectively catalyze the dearomatizing
cyclization of a naphthyl amide. Unfortunately, these precatalysts
were not effective in delivering the dearomatizing cyclization
products in high enantioselectivities, but they may be useful in
other iodine(I/III)-catalyzed processes.
2
1
7
868, 1737, 1641, 1573, 1557, 1519, 1463, 1433, 1367, 1273,
-1 1 6
255, 1205, 1155, 1016 cm ; H NMR (DMSO-d , 400 MHz)
.84-7.78 (m, 2H), 7.72 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.28 (t,
J = 8.1 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 4.26-4.21 (m, 1H), 3.65
(
6
s, 3H), 1.73-1.66 (m, 1H), 1.58 (t, J = 7.3 Hz, 2H), 0.93 (d, J =
13
6
.5 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H); C NMR (DMSO-d , 100
MHz) 173.7, 154.7, 140.3, 138.9, 128.5, 124.3, 122.0, 90.0, 51.8,
+
5
1.0, 40.6, 24.3, 22.7, 21.5; HRMS [M+H] m/z calc’d for
C H IN O 391.0513, found 391.0510.
14
20
2
3
3
.3.2. Benzyl ((2-iodophenyl)carbamoyl)-L-
alaninate (13b)
Pale yellow solid (0.37 g, 88%). M.p. 161-163 °C; IR 3299,
3
060, 2979, 2605, 2498, 1720, 1633, 1556, 1512, 1463, 1452,

5
−
1
1
6
1
4
1
2
432, 1318, 1291, 1221, 1164, 1097 cm ; H NMR (DMSO-d ,
00 MHz) 7.84-7.79 (m, 2H), 7.74 (s, 1H), 7.58 (d, J = 6.9 Hz,
H), 7.39-7.27 (m, 6H), 6.77 (t, J = 7.4 Hz, 1H), 5.20-5.11 (m,
6.98 (d, J = 8.1 Hz, 2H), 4.90 (br s, 2H), 3.85-3.78 (m, 2H),
13
3.43-3.32 (m, 4H), 2.91-2.81 (m, 2H), 2.73-2.65 (m, 2H);
C
6
NMR (DMSO-d , 100 MHz) 154.7, 141.2, 139.2, 129.3, 128.2,
127.7, 125.9, 117.2, 89.5, 62.4, 52.8, 37.3; HRMS [M+H] m/z
13
+
H), 4.33-4.24 (m, 1H), 1.35 (d, J = 7.4 Hz, 3H); C NMR
(DMSO-d6, 100 MHz) 173.2, 154.5, 140.3, 138.9, 136.1, 128.5,
calc’d for C H IN O 589.1306, found 589.1321.
26
30
4
4
1
28.5, 128.0, 127.7, 124.4, 122.1, 90.1, 65.9, 48.5, 17.6; HRMS
+
3.5.4. 1,1'-(2-iodo-1,3-phenylene)bis(3-((1S,2R)-2-
hydroxy-1,2-diphenylethyl)urea) (16d)
[
M+H] m/z calc’d for C H IN O 425.0357, found 425.0359.
17 18 2 3
3
.4. Preparation of 2-iodo-1,3-diisocyanatobenzene 17
White solid (370 mg, 74%). M.p. 221-223 °C; IR 3343, 3213,
2
1
981, 1647, 1587, 1556, 1503, 1465, 1396, 1276, 1231, 1068,
047 cm ; H NMR (DMSO-d , 400 MHz) 7.98 (s, 2H), 7.67 (d,
A solution of 2-iodoisophthalic acid 19 (1.5 g, 5.1 mmol) in
thionyl chloride (40 mL) was heated to reflux for 2 h then
concentrated under reduced pressure to afford 2-iodoisophthaloyl
-1 1 6
J = 8.8 Hz, 2H), 7.47 (d, J = 7.4 Hz, 4H), 7.42 (d, J = 7.4 Hz,
4
6
H), 7.36-7.32 (m, 8H), 7.26-7.20 (m, 4H), 7.07-7.06 (m, 2H),
chloride. This crude mixture was dissolved in THF (15 mL),
.99-6.93 (m, 1H), 5.67 (d, J = 4.1 Hz, 2H), 4.90-4.83 (m, 4H);
o
cooled to 0 C and NaN (2.2 g, 34 mmol) dissolved in water (8
13
6
3
C NMR (DMSO-d , 100 MHz) 154.7, 143.7, 142.8, 141.1,
mL) was added. After 2 h, the reaction mixture was quenched
1
5
27.8, 127.6, 127.4, 127.1, 126.8, 126.6, 126.4, 117.6, 90.0, 75.6,
with saturated aqueous NaHCO (10 mL) solution and extracted
+
3
9.1; HRMS [M+Na] m/z calc’d for C H IN O Na 735.1439,
36
33
4
4
with toluene (30 mL). This was dried over MgSO4 and
evaporated to half under reduced pressure to give a toluene
solution of 2-iodoisophthaloyl diazide 24. Without further
purification, the crude mixture was heated at reflux for 2 hours
and then concentrated to ~3 mL to afford 17 as a light brown
solution (1.42 g, 96% – determined by NMR). The progress of
the reaction was monitored by IR. IR 3370, 3024, 2251, 2141,
found 735.1441.
3.5.5. 1,1'-(2-iodo-1,3-phenylene)bis(3-((1R,2S)-1-
hydroxy-2,3-dihydro-1H-inden-2-yl)urea) (16e)
Off-white solid (0.52 g, 63%). M.p. 247-248 °C; IR 3318,
3240, 2912, 1682, 1632, 1550, 1465, 1400, 1359, 1231, 1142,
1047 cm ; H NMR (DMSO-d , 400 MHz) 8.09 (s, 2H), 7.46 (d,
J = 8.1 Hz, 2H), 7.29-7.18 (m, 11H), 5.23 (d, J = 4.1 Hz, 2H),
5.11 (dd, J = 8.7, 4.9 Hz, 2H), 4.47 (q, J = 4.5 Hz, 2H), 3.07 (dd,
J = 16.2, 4.6 Hz, 2H), 2.81 (d, J = 16.1 Hz, 2H); C NMR
(DMSO-d , 100 MHz) 155.5, 143.2, 141.4, 140.5, 127.8, 127.1,
1
-
1
1
6
−1 1
1
4
(
723, 1573, 1494, 1396, 1214, 781, 728 cm ; H NMR (CDCl ,
3
13
00 MHz) 7.20-7.30 (m, 1H), 6.93 (d, J = 8.0 Hz, 2H); C NMR
1
3
CDCl , 100 MHz) 138.2, 130.0, 129.8, 122.2, 97.2; HRMS [M-
3
+
6
CO+3H] m/z calc’d for C H IN O 260.9519, found 260.9516.
7
6
2
+
26.3, 124.9, 124.1, 118.3, 90.9, 72.3, 57.6; HRMS [M+H] m/z
3
.5. Preparation of bisureas 16
calc’d for C H IN O 585.0993, found 585.0989.
26
26
4
4
To a solution of 2-iodo-1,3-diisocyanatobenzene 17 (0.70 mL,
.3 mmol, 1 equiv) in THF (60 mL) at 0 C was added dropwise
3
.5.6. (2S,2'S)-2,2'-((((2-iodo-1,3-
o
4
phenylene)bis(azanediyl))bis(carbonyl))bis(azanedi
a solution of amine (1.5 g, 9.5 mmol, 2.2 equiv) in THF (10 mL).
The ice bath was removed and the reaction mixture was stirred
for 3-4 hours or until TLC analysis showed completion of the
reaction. Then, the reaction mixture was concentrated under
reduced pressure and the residue washed with hexanes multiple
times. Recrystallization from ethyl acetate and ethanol provided
the bisurea 16. Typically, solvents could not be completely
removed from these compounds.
yl))bis(3-phenylpropanoic acid) (16f)
Pale-yellow solid (0.76 g, 70%). M.p. 227-229 °C; IR 3217,
3
1
7
025, 2890, 1714, 1638, 1547, 1494, 1464, 1407, 1275, 1214,
075 cm ; H NMR (DMSO-d , 400 MHz) 7.88 (s, 2H), 7.33-
-1 1 6
.21 (m, 16H), 7.15-7.11 (m, 1H), 4.48-4.40 (m, 2H), 3.14-3.07
13
6
(m, 2H), 2.98-2.90 (m, 2H); C NMR (DMSO-d , 100 MHz)
1
9
73.5, 154.6, 141.0, 137.3, 136.6, 129.5, 128.5, 126.5, 117.8,
0.1, 54.0, 37.6; HRMS: [M+H] m/z calc’d for C H IN O
+
2
6
26
4
6
3
.5.1. 1,1'-(2-iodo-1,3-phenylene)bis(3-((S)-1-
617.0892, found 617.0898.
hydroxypropan-2-yl)urea)(16a)
3
.5.7. (2S,2'S)-((((2-iodo-1,3-
White solid. (0.50 g, 81%). M.p. 249-250 °C; IR 3284, 2980,
phenylene)bis(azanediyl))bis(carbonyl))bis(azanedi
yl))bis(3-phenylpropane-2,1-diyl) dibenzoate (16g)
-
1
1
6
2
7
6
3
851, 1632, 1162, 1035 cm ; H NMR (DMSO-d , 400 MHz)
.60 (s, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.14 (t, J = 8.1 Hz, 1H),
.89 (d, J = 7.6 Hz, 2H), 4.77 (br s, 2H), 3.70-3.65 (m, 2H), 3.42-
Yellow solid (120 mg, 49%). M.p. 230-232 °C; IR 3288,
064, 2923, 2852, 1716, 1641, 1538 cm ; H NMR (DMSO-d ,
00 MHz) 8.05-8.02 (m, 4H), 7.70-7.66 (m, 2H), 7.57-7.52 (m,
H), 7.41-7.37 (m, 2H), 7.33-7.30 (m, 10H), 7.26-7.21 (m, 4H),
-1
1
6
3
4
4
7
13
6
.28 (m, 4H), 1.08 (d, J = 6.8 Hz, 6H); C NMR (DMSO-d , 100
MHz) 154.7, 141.2, 127.8, 117.1, 89.3, 64.8, 47.0, 17.8; HRMS
+
[
M+H] m/z calc’d for C H IN O 437.0680, found 437.0698.
13
14
22
4
4
.14-7.08 (m, 1H), 4.36-4.17 (m, 6H), 2.99-2.84 (m, 4H);
C
6
NMR (DMSO-d , 100 MHz) 165.7, 154.7, 149.2, 138.2, 133.5,
129.7, 129.4, 129.2, 128.8, 128.4, 128.0, 126.3, 119.3, 87.9, 66.1,
4
3
.5.2. 1,1'-(2-iodo-1,3-phenylene)bis(3-((S)-1-
hydroxybutan-2-yl)urea) (16b)
+
9.8, 37.4; HRMS [M+H] m/z calc’d for C H IN O 797.1831,
Pale yellow solid (0.60 g, 90%). M.p. 252-254 °C; IR 3290,
40 38
4
6
found 797.1835.
2
1
7
962, 2930, 2873, 2355, 1633, 1556, 1463, 1410, 1274, 1223,
074, 1018 cm ; H NMR (DMSO-d , 400 MHz) 7.62 (s, 2H),
.38 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1
-1 1 6
3
.6. Preparation of 1-((S)-1-hydroxy-3-phenylpropan-2-yl)-3-
((S)-1-phenylpropyl)urea 28
Hz, 2H), 4.72 (br s, 2H), 3.56-3.42 (m, 4H), 3.35-3.32 (m, 2H),
1
.64-1.54 (m, 2H), 1.43-1.31 (m, 2H), 0.89 (t, J = 7.4 Hz, 6H);
To a solution of (S)-(1-isocyanatopropyl)benzene 26 (0.50 g,
13
6
o
C NMR (DMSO-d , 100 MHz) 155.0, 141.3, 127.8, 117.1, 89.3,
3.1 mmol, 1 equiv) in THF (40 mL) at 0 C was added dropwise
a solution of amine 27 (0.52 g, 3.4 mmol, 1.1 equiv) in THF (10
mL). The ice bath was removed and the reaction mixture was
stirred for 4 hours. The reaction mixture was concentrated under
reduced pressure and the residue was washed with hexanes
multiple times and then purified by flash chromatography (silica
gel; 1:1 petroleum ether/EtOAc) to provide 28 as a white solid
+
6
3.0, 52.5, 24.2, 10.5; HRMS [M+H] m/z calc’d for
C H IN O 465.0993, found 465.0990.
16
26
4
4
3
.5.3. 1,1'-(2-iodo-1,3-phenylene)bis(3-((S)-1-
hydroxy-3-phenylpropan-2-yl)urea) (16c)
Yellow solid (1.7 g, 85%). M.p. 265-266 °C; IR 3297, 3024,
-
1
1
6
2
919, 1634, 1548, 1465, 1271 cm ; H NMR (DMSO-d , 400
(
1.0 g, 99%). M.p. 130-131 °C; IR 3336, 3026, 2927, 2356, 2341,
MHz) 7.64 (s, 2H), 7.32-7.20 (m, 12H), 7.10 (t, J = 8.1 Hz, 1H),

6
Tetrahedron
-1 1
2
3
4
.
.
.
Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura, T.
Angew. Chem. Int. Ed. 2010, 49, 7068−7071.
Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010,
1
610, 1586, 1565, 1493, 1449, 1380, 1253, 1073, 1046 cm ; H
6
NMR (DMSO-d , 400 MHz) 7.32-7.14 (m, 10H), 6.40 (d, J = 8.6
Hz, 1H), 5.79 (d, J = 8.6 Hz, 1H), 4.83 (br s, 1H), 4.50 (q, J = 7.3
Hz, 1H), 3.71-3.67 (m, 1H), 3.35-3.25 (m, 2H), 2.80-2.75 (m,
4
9, 2175–2177.
For example, see: (a) Uyanik, M,; Yasui, T.; Ishihara, K. Angew.
Chem. Int. Ed. 2013, 52, 9215-9218; (b) Jain, N.; Xu, S.;
Ciufolini, M. A. Chem. Eur. J. 2017, 23, 4542-4546.
Dohi, T.; Takenaga, N.; Nakae, T.; Toyoda, Y.; Yamasaki, Y.;
Shiro, M.; Fujioka, H.; Maruyama, A.; Kita, Y. J. Am. Chem. Soc.
1
3
1
H), 2.62-2.57 (m, 1H), 1.67-1.53 (m, 2H), 0.80 (t, J = 7.3 Hz,
H); C NMR (DMSO-d , 100 MHz) 157.2, 144.6, 139.2, 129.2,
28.1, 128.1, 126.2, 62.5, 54.3, 52.4, 37.2, 30.0, 10.6; HRMS
13 6
5
.
+
[
M+H] m/z calc’d for C H N O 313.1911, found 313.1909.
19
25
2
2
2
013, 135, 4558−4566.
6
7
.
.
Antien, K.; Pouységu, L.; Deffieux, D.; Massip, S.; Peixoto, P. A.;
Quideau, S. Chem. Eur. J. 2019, 25, 2852−2858.
Hashimoto, T.; Shimazaki, Y.; Omatsu, Y.; Maruoka, K. Angew.
Chem. Int. Ed. 2018, 57, 7200-7204.
3
.7. Preparation of bis((S)-3-phenyl-2-(3-((S)-1-
phenylpropyl)ureido)propyl)(2-iodo-1,3-phenylene)dicarbamate
2
9
8
9
.
.
Murray, S. J.; Ibrahim, H. Chem. Commun. 2015, 51, 2376−2379.
Rodríguez, A.; Moran, W. J. Synthesis 2012, 44, 1178-1182.
2
-Iodo-1,3-diisocyanatobenzene 17 (350 mg, 1.2 mmol, 1
equiv – as a solution in toluene) and triethylamine (0.37 mL, 2.7
10. Abazid, A. H.; Nachtsheim, B. J. Angew. Chem. Int. Ed. 2020, 59,
mmol, 2.2 equiv) were dissolved in dichloromethane (30 mL)
1479-1484.
o
1
1
1. Tariq, M. U.; Moran, W. J. Eur. J. Org. Chem. 2020, 5153-5160.
2. For the synthesis of iodoarene 1a, see: Banik, S. M.; Medley, J.
W.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 5000-5003.
3. Haubenreisser, S; Wöste, T. H.; Martínez, C.; Ishihara, K.; Muñiz,
K. Angew. Chem. Int. Ed. 2016, 55, 413–417.
and cooled to 0 C under N . Urea 28 (0.75 g, 2.4 mmol, 2.2
2
equiv) was dissolved in dichloromethane (20 mL) in a separate
flask and added to the first solution dropwise over 10 minutes.
The reaction mixture was stirred overnight at room temperature
and then concentrated under reduced pressure. The residue was
quenched with 1 N HCl (20 mL) and extracted with EtOAc (20
1
14. Wechsel, R.; Raftery, J.; Cavagnat, D.; Guichard, G.; Clayden, J.
Angew. Chem. Int. Ed. 2016, 55, 9657–9661.
1
5. Bécart, D.; Diemer, V.; Salaün, A.; Oiarbide, M.; Nelli, Y. R.;
Kauffmann, B.; Fischer, L.; Palomo, C.; Guichard, G. J. Am.
Chem. Soc. 2017, 139, 12524-12532.
mL x 3), dried over MgSO and concentrated under reduced
4
pressure. Recrystallization from CH Cl /EtOAc afforded 29 as a
2
2
dark brown solid (0.73 g, 65%). M.p. 249-251 °C; IR 3270, 3026,
16. For examples of the synthesis of related iodoarenes, see: (a) Gaux,
2
1
7
4
1
961, 1702, 1633, 1584, 1519, 1461, 1398, 1202, 1109, 1109,
B.; Le Hénaff, P. C. R. Acad. Sc. Serie C 1973, 277, 1033-1035;
-
1
1
6
(b) Hayashi, M.; Sai, H.; Horikawa, H. Heterocycles 1998, 48,
018 cm ; H NMR (DMSO-d , 400 MHz) 9.01 (s, 2H), 7.32-
.17 (m, 23H), 6.43 (d, J = 8.0 Hz, 2H), 5.86 (d, J = 8.0 Hz, 2H),
.56-4.49 (m, 2H), 4.02-3.95 (m, 6H), 2.83-2.70 (m, 4H), 1.67-
1
331-1335; (c) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li,
X.; Aluisio, L. E.; Phuong, V. K.; Dvorak, C. A.; Lovenberg, T.
W.; Carruthers, N. I.; Jones, T. K. Bioorg. Med. Chem. Lett. 2004,
13
6
.59 (m, 4H), 0.79 (t, J = 7.0 Hz, 6H); C NMR (DMSO-d , 100
1
4, 4225-4229; (d) Nickerson, D. M.; Mattson, A. E. Chem. Eur.
MHz) 157.0, 154.2, 144.5, 140.6, 138.2, 129.3, 128.5, 128.5,
28.1, 126.4, 126.2, 83.2, 65.8, 54.4, 49.8, 37.3, 29.9, 10.7;
J. 2012, 18, 8310-8314; (e) Wu, J.; Wang, C.; Häberli, C.; White,
K. L.; Shackleford, D. M.; Chen, G.; Dong, Y.; Charman, S. A.;
Keiser, J.; Vennerstrom, J. L. Bioorg. Med. Chem. Lett. 2018, 28,
1
+
HRMS [M+Na] m/z calc’d for C H IN NaO 933.2807, found
46
51
6
6
3
648-3651; (f) Ruan, B.; Zhang, Y.; Tadesse, S.; Preston, S.; Taki,
9
33.2813.
A. C.; Jabbar, A.; Hofmann, A.; Jiao, Y.; Garcia-Bustos, J.;
Harjani, J.; Le, T. G.; Varghese, S.; Teguh, S.; Xie, Y.; Odiba, J.;
Hu, M.; Gasser, R. B.; Baell, J. Eur. J. Med. Chem. 2020, 190,
Acknowledgments
1
12100.
1
1
7. Zeng, F.; Alper, H. Org. Lett. 2010, 12, 3642-3644.
8. Jones, I. M.; Hamilton, A. D. Angew. Chem. Int. Ed. 2011, 50,
We thank the University of Huddersfield for funding (fee-
waiver scholarship to MUT). We thank Mirdyul Das (University
of Huddersfield) for the preparation of iodoarene 1a.
4
597-4600.
1
2
9. Rewcastle, G. W.; Denny, W. A. Synthesis 1985, 217-220.
0. Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T.
J. Nat. Rev. Chem. 2017, 1, 0088.
References and notes
1
.
For reviews, see: (a) Parra, A. Chem. Rev. 2019, 119, 12033-
2088; (b) Flores, A.; Cots, E.; Bergès, J.; Muñiz, K. Adv. Synth.
1
Appendix A. Supplementary Material
Catal. 2019, 361, 2−25; (c) Ghosh, S.; Pradhan, S.; Chatterjee, I.
Beilstein J. Org. Chem. 2018, 14, 1244−1262; (d) Fujita, M.
Tetrahedron Lett. 2017, 58, 4409-4419; (e) Berthiol, F. Synthesis
Supplementary data to this article can be found online at
2
2
015, 47, 587−603; (f) Kumar, R.; Wirth, T. Top. Curr. Chem.
015, 373, 243−261.

Highlights
‹
‹
‹
Preparation of novel chiral C and C symmetric iodoarenes
1 2
Robust bidirectional synthetic strategy
Evaluation as catalysts in iodine(I/III) mediated cyclization

Supporting Information
Design and synthesis of chiral urea-derived iodoarenes and
their assessment in the enantioselective dearomatizing
cyclization of a naphthyl amide
a
a
M. Umair Tariq and Wesley J Moran *
a
Department of Chemistry, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, U.K.
E-mail: w.j.moran@hud.ac.uk
Table of Contents
1
13
H and C NMR spectra of novel compounds
S2
S1

S2

S3

S4

S5

Somewhat unstable
bisisocyanate 17 was
not purified after
workup, and was kept
as a toluene solution
S6

Somewhat unstable
bisisocyanate 17 was
not purified after
workup, and was kept
as a toluene solution
S7

S8

S9

S10

S11

Solvents, especially THF, could
not always be completely
removed from these ureas
S12

S13

S14

S15

S16

THF
THF
S17

O
I
O
H
H
H
H
N
N
N
N
HO
OH
O
O
Ph
Ph
16f
S18

O
I
O
H
H
H
H
N
N
N
N
HO
OH
O
O
Ph
Ph
16f
THF
THF
S19

S20

S21