Synthesis, characterization, and initial reaction study of two new bicyclic hypervalent iodine(III) reagents

Article abstract of DOI:10.1016/j.tetlet.2014.03.034

The synthesis of two new bicyclic hypervalent iodine(III) reagents 5 and 6 is described along with their corresponding X-ray crystal structures for the first time. A detailed comparison in the bond lengths and bond angles of reported bicyclic hypervalent

Full text of DOI:10.1016/j.tetlet.2014.03.034

Tetrahedron Letters 55 (2014) 2687–2690
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis, characterization, and initial reaction study
of two new bicyclic hypervalent iodine(III) reagents
⇑
Wen-Chao Gao , Chi Zhang
The State Key Laboratory of Elemento-Organic Chemistry, The Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of two new bicyclic hypervalent iodine(III) reagents 5 and 6 is described along with their
corresponding X-ray crystal structures for the first time. A detailed comparison in the bond lengths and
bond angles of reported bicyclic hypervalent iodine(III) reagents is also presented. Furthermore, an initial
study shows that these two hypervalent iodine(III) reagents could promote the dipeptide coupling
reaction.
Received 17 January 2014
Revised 2 March 2014
Accepted 6 March 2014
Available online 13 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Hypervalent iodine reagent
Bicyclic iodinane
X-ray diffraction
Structural comparison
During the past decades, the chemistry of hypervalent iodine
reagents has attracted significant research interest.1 Various types
of hypervalent iodine(III) compounds (k3-iodanes) have been re-
ported and some of them have been applied for diverse useful oxi-
dative transformations due to their high chemoselectivity, mild
reaction conditions, and environmentally benign nature. Among
these reagents, monocyclic or bicyclic hypervalent iodine(III) com-
pounds represent an especially important class of reagents, which
facilitate diverse organic transformations. Monocyclic hypervalent
iodine(III) reagents derived from 2-iodobenzoic acid such as
O
I
O
O
I
O
O
O
O
O
F3C
F3C
CF3
CF3
I
O
O
R
4
3
1
( )
R = CH3
(six-membered)
(five-membered)
2
)
R = C(CH3)3
(
Figure 1. Examples of bicyclic hypervalent iodine(III) reagents.
be functioned as an efficient coupling reagent to promote the di-
rect esterification, direct amidation, and peptide coupling without
racemization.9
1-(tert-butylperoxy)-1,2-benziodoxol-3(1H)-one,2
1-azido-1,2-
benziodoxol-3(1H)-one,3 Togni reagent,4 and 1-chloro-1,2-benzio-
doxol-3(1H)-one5 have been well studied and applied in the
synthetic chemistry. As for the bicyclic ones, several reagents have
also been reported due to their unique structural characters, and
examples include (dialkoxy)iodinanes and (dilactone)iodinanes
(Fig. 1). In 1982, Martin and co-workers reported the synthesis of
dialkoxyiodinanes 1 and 2, which bore two hexafluoroisopropyl
ether rings,6 and the X-ray analysis of (dialkoxy)iodinane 2 indi-
cated the two five-membered ether rings were not exactly copla-
nar.7 However, because of the complicated synthesis routes,
there is no report about their synthetic utility. In 1965, Agosta
firstly reported the preparation of iodosodilactone 3 and 4, which
were hardly soluble in organic solvent except DMSO;8 quite
recently, the X-ray crystal structure of iodosodilactone 3 was
obtained by Zhang and co-workers, and it was found that 3 could
As the continuous research in bicyclic hypervalent iodine re-
agents, herein, we report the synthesis of two new types of bicyclic
hypervalent iodine(III) reagents (Fig. 2): one is the (dialkoxy)iod-
inane 5 bearing two symmetric isopropyl ether rings; the other is
the lactone-ether-mixed iodinane 6, including a five-membered
ether ring and a five-membered lactone ring. These two reagents
are readily accessed from the commercially available materials,
and both of their X-ray structures are disclosed for the first time.
The synthesis route for iodinane 5 began with the esterification
of the commercially available 2-iodoisophthalic acid (7), which
gave dimethyl 2-iodoisophthalate (8) in 90% yield. When subject-
O
I
O
O
I
O
O
5
6
⇑
Corresponding author. Tel.: +86 02223502382.
E-mail address: gaowenchao@mail.nankai.edu.cn (W.-C. Gao).
Figure 2. Two new kinds of bicyclic hypervalent iodine(III) reagents.
http://dx.doi.org/10.1016/j.tetlet.2014.03.034
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2688
W.-C. Gao, C. Zhang / Tetrahedron Letters 55 (2014) 2687–2690
OH I OH
O
O
I
O
O
I
O
O
I
O
OMeI OMe
C1
C1
C1
SOCl2 (10 eq)
MeOH, 60 o
O
O O
O
O
O
C
5
6
3
7
8
, 90%
δ 105.5 ppm δ 115.2 ppm δ 125.7 ppm
CH3MgI (5 eq)
I
2 (3 eq)
Et2O, reflux
Figure 3. NMR signals of the carbon atom attached to the iodine atom.
OH I OH
OH I OMe
O
+
10
, 22%
9, 64%
tBuOCl (1.5 eq)
CHCl3, 1.5 h
O
I
O
5, 81%
Scheme 1. Synthesis of iodinane 5.
Figure 4. X-ray crystal structure of iodinane 5.
ing 8 to the conventional protocol for the preparation of tertiary
alcohol,10 the reaction of 8 with methyl Grignard reagent resulted
in the loss of the iodine atom in the diol product. Therefore, the
additional molecular iodine was required to trap the generated
phenyl cation. The desired diol 9 was produced in 64% yield, along
with a minor product, methyl 3-(2-hydroxypropan-2-yl)-2-iodo-
benzoate (10),11 which could serve as the precursor of iodinane
6. After the diol 9 reacted with tert-butyl hypochlorite (tBuOCl),
the (dialkoxy)iodinane 5 was afforded in 81% yield (Scheme 1).12
Iodinane 5 is a stable compound, which could be stored for several
months at room temperature without any detectable decomposi-
tion. Starting from the benzoate 10, the other bicyclic iodinane 6
could be readily accessed after hydrolysis with LiOH followed by
the oxidation with tBuOCl (Scheme 2).13
These two bicyclic hypervalent iodine(III) compounds are iden-
tified on the basis of NMR spectroscopic data, high resolution mass
spectrometry, and single crystal X-ray analysis. 13C NMR analysis
indicated a downfield shift of the signal for the carbon atom
attached to the iodine atom: the shift from d 94.2 ppm to
d 105.5 ppm in the iodinane 5, and the shift from d 90.7 ppm to
d 115.2 ppm in the iodinane 6, which are consistent with what is
observed in other hypervalent iodine(III) compounds.14 It was
noted that there was a 10-ppm motion to the downfield in the
bicyclic hypervalent iodine(III) compounds when an ether ring is
replaced by a lactone ring (Fig. 3).
Both of these two bicyclic iodinanes have good solubility in
commonly organic solvents such as dichloromethane (5, 4 mg/
mL; 6, 2.8 mg/mL) and ethyl acetate (5, 4.5 mg/mL; 6, 4.4 mg/
mL). The single crystal of iodinane 5 was grown from the mixed
solvent of dichloromethane and ethyl acetate, and the single crys-
tal of iodinane 6 was obtained in the solvent of dichloromethane.
As is observed in iodosodilactone 3, these two crystal structures
have roughly coplanar geometry. For the structure of 5 (Fig. 4),
the five-membered rings are slightly distorted from planarity (tor-
sion angles O1–I1–C1–C2 = 9.27(15)°, O2–I1–C1–C6 = 8.10(16)°);
when one of the ether rings is replaced by the lactone ring, just
as the structure of iodinane 6 (Fig. 5), the lactone ring bends more
slightly (torsion angle O1–I1–C1–C6 = 8.77(19)°, O2–I1–C1–
C2 = 2.67(19)°). And, as for the iodosodilactone 3 bearing two
lactone rings, all of the lactone atoms are almost coplanar (torsion
angles 0.4(4)° and 0.5(4)° respectively).
Figure 5. X-ray crystal structure of iodinane 6.
Table 1
Selected intramolecular bond lengths and bond angles of bicyclic hypervalent
iodine(III) reagents
Entry
Structure
O–I–O angle/°
I–O bond length/Å
Ref.
O
I
O
F3C
F3C
CF3
CF3
2.113(3)
2.077(3)
1
158.2(1)
7
tBu
2
O
O
I
O
2.0919(15)
2.0994(15)
2
3
4
157.46(6)
156.28(9)
155.21(14)
This work
This work
9
5
I
O
2.047(2)
2.212(3)
O
6
O
O
I
O
2.126(4)
2.141(4)
O
3
The O–I–O angle is also an important parameter in the struc-
tural analysis of hypervalent iodine reagents. To give a clear com-
parison, the O–I–O angles of existing bicyclic hypervalent
iodine(III) reagents are listed in Table 1. A slightly greater deviation
from 180° is found when all the fluorine atoms are replaced by
hydrogen atoms (Table 1, entry 1 vs entry 2). The change of ring
system from an ester ring to a lactone ring also affects the O–I–O
angle, which becomes smaller when the lactone ring is introduced
(entry 2 vs entry 3; entry 3 vs entry 4).
Another structural parameter, the O–I bond lengths of iodinane
5 and 6, are also revealed according to the X-ray analysis (Table 1).
Compared with bicyclic iodinane 2, the intramolecular I–O bonds
in the compound 5 are more equal (entry 1 vs entry 2). And, intro-
ducing a lactone ring would break this balance. For example, the
intramolecular I–O bond length in the lactone ring of compound
6 is 2.212(3) Å, which is longer than the I–O bond length in the
ether ring (2.074(2) Å). A comparison of the intramolecular I–O
O
I
O
OH I OCH
O
3 LiOH (3 eq)
MeOH, rt
tBuOCl (1.5 eq)
CHCl3
O
10
6, 53% for two steps
Scheme 2. Synthesis of iodinane 6.

W.-C. Gao, C. Zhang / Tetrahedron Letters 55 (2014) 2687–2690
2689
Table 2
Synthesis of dipeptide Z-L-Leu-L-Ala-OMe using three bicyclic hypervalent iodine(III)
reagentsa
Iodinane (1.2 eq)
O
NHCbz
COOH
11a
Ph3P (1 eq)
O
H
N
+
H2N
OMe
DMAP (1.2 eq)
CbzHN
OMe
CHCl3, 60 o
C
O
12a (1 equiv)
13aa
Entry
Iodinane
Yieldb (%)
Time (h)
D/DLc (%)
1
2
3
6
5
6
5
84
6
24
24
10
10
<0.1
<0.1
<0.1
<0.1
<0.1
70 (86)d
58 (80)d
69 (88)d
55 (82)d
3
4e
5e
Figure 6. Intermolecular interaction between 5 and its neighboring molecule.
a
Reaction conditions: 11a (1.0 mmol), 12a (1.0 mmol), Iodinane (1.2 mmol),
DMAP (1.2 mmol), Ph3P (1.0 mmol), in CHCl3 (10 mL), 60 °C.
b
Isolated yield.
c
The optical purity of products was determined by HPLC.
The data in the parentheses are the chemical yields based on the recovery of
d
11a.
e
The reaction was run at 80 °C in EtOAc.
as efficient as iodosodilactone 3 (Table 2, entries 2 and 3 vs entry
1). Even though the reaction time was prolonged to 24 h, the start-
ing materials were still not consumed. Furthermore, the reaction
was also tested at higher temperature, while no better results were
obtained (entries 4 and 5). Compared with iodosodilactone 3, the
iodine center was more electron rich in compound 5 or 6, which
may cause their weak reactivity for the present transformation. It
was noted that there was no detectable racemization in these cou-
pling reactions mediated by three bicyclic hypervalent iodine(III)
reagents.
Figure 7. Intermolecular interaction between 6 and its neighboring molecule.
In conclusion, two new bicyclic hypervalent iodine(III) reagents
5 and 6 have been successfully prepared and characterized by
spectroscopy and single crystal X-ray analysis. By the structural
comparison with other reported bicyclic hypervalent iodine(III) re-
agents, the unique structural features of these two iodinanes are
disclosed. Furthermore, these two bicyclic hypervalent iodine(III)
reagents are readily available and soluble in common organic sol-
vents, rendering them the oxidative potential in organic synthesis.
In an initial reactivity study, these two bicyclic reagents can pro-
mote the dipeptide coupling reaction without racemization. The
further reactivity exploration of two reagents is currently in
progress.
bonds with the known bicyclic hypervalent iodine(III) reagents is
given in Table 1. The I–O bond lengths in the five-membered rings,
regardless of an ether ring or a lactone ring, are generally found in
the range of 2.07 Å to 2.22 Å.
Both of the molecules 5 and 6 are aggregated in the solid state
to form dimmers held together by intermolecular IÁ Á ÁO secondary
bonds, which is consistent with what is observed in other hyperva-
lent iodine compounds.7 In the iodinane 5 (Fig. 6), the distance be-
tween the iodine atom and its nearest oxygen atom of the neighbor
molecule (IÁ Á ÁO 2.89 Å) is shorter than the intermolecular IÁ Á ÁO sec-
ondary bond in the iodinane 2 (IÁ Á ÁO 3.00 Å). As for iodinane 6
(Fig. 7), although two ring types exist, only one type of the inter-
molecular IÁ Á ÁO secondary bond, linking the iodine atom and the
oxygen atom in the ether ring of the neighbor molecule (IÁ Á ÁO
2.79 Å), is observed, while the bond distance (3.81 Å) between
the iodine atom and the oxygen atom in the nearest lactone ring
is out of the sum of van der Waals radii (3.5 Å).15 However, when
both of two ether rings were replaced by the lactone rings, there
are two types of intermolecular secondary bonding found in the
iodosodilactone 3. One is the interaction between the iodine atom
and the oxygen atom in the cycle of a neighboring lactone ring
(IÁ Á ÁO 3.17 Å), and the other secondary bond is between the iodine
atom and the carbonyl oxygen of the neighboring lactone ring
(IÁ Á ÁO 2.84 Å). Accordingly, the molecules of iodosodilactone 3
are linked together via two I–O secondary bonds and hydrogen
bonds to form a dense network, which led to the poor solubility
different from iodinane 5 and 6.
Supplementary data
Crystallographic data for the structural analysis of 5 and 6 have
been deposited in the Cambridge Crystallographic Data Centre
(CCDC No. 959777 and 959973). Copies of this information can
be obtained free of charge via www.ccdc.cam.ac.uk.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
034.
References and notes
1. (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178; (b) Varvoglis, A.
Hypervalent iodine in organic synthesis; Academic: San Diego, CA, 1997; (c)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584; (d) Wirth, T.
Hypervalent iodine chemistry: modern developments in organic synthesis; topics in
current chemistry series 224; Springer: Berlin-Tokyo, 2003; (e) Wirth, T. Angew.
Chem., Int. Ed. 2005, 44, 3656–3665; (f) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2008, 108, 5299–5358; (g) Zhdankin, V. V. ARKIVOC 2009, 1, 1–62; (h) Brand, J.
P.; González, D. F.; Nicolai, S.; Waser, J. Chem. Commun. 2011, 102–115; (i)
Merritt, E. A.; Olofsson, B. Synthesis 2011, 517–538.
Since the iodosodilactone 3 could function as a coupling reagent
for dipeptide coupling reaction,9 compound 5 and 6 were also
examined for the dipeptide coupling reaction by using N-Cbz-leu-
cine and glycine methyl ester under the standard conditions
(1.2 equiv of oxidant, 1 equiv of Ph3P, 1.2 equiv of DMAP, CHCl3,
60 °C). All of these three bicyclic reagents could promote the
dipeptide coupling reaction, while the iodinane 5 and 6 were not
2. (a) Ochiai, M.; Ito, T.; Masaki, Y. J. Am. Chem. Soc. 1992, 114, 6269–6270; (b)
Ochiai, M.; Ito, T.; Takahashi, H.; Nakanishi, A.; Toyonari, M.; Sueda, T.; Goto, S.;
Shiro, M. J. Am. Chem. Soc. 1996, 118, 7716–7730.

2690
W.-C. Gao, C. Zhang / Tetrahedron Letters 55 (2014) 2687–2690
3. (a) Krasutsky, A. P.; Kuehl, C. J.; Zhdankin, V. V. Synlett 1995, 1081–1082; (b)
Zhdankin, V. V.; Krasutsky, A. P.; Kuehl, C. J.; Simonsen, A. J.; Woodward, J. K.;
Mismash, B.; Bolz, J. T. J. Am. Chem. Soc. 1996, 118, 5192–5197.
4. Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579–2586.
5. (a) Li, X.-Q.; Zhang, C. Synthesis 2009, 1103–1109; (b) Meyer, V.; Wachter, W.
Ber 1892, 25, 2632–2635.
12. To the solution of 9 (240 mg, 0.75 mmol) in chloroform (8 mL) was added the
freshly prepared tBuOCl (122 mg, 1.1 mmol). The reaction was stirred at room
temperature until 9 was completely consumed. After the solvent was removed
in vacuo, the crude product was purified by chromatography to give iodinane
5. Yield: 81%; white solid; mp: 169–171 °C; 1H NMR (CDCl3, 400 MHz): d 7.53
(t, 1H, J = 7.6 Hz), 7.19 (d, 2H, J = 7.6 Hz), 1.46 (s, 12H); 13C NMR (CDCl3,
6. Nguyen, T. T.; Amey, R. L.; Martin, J. C. J. Org. Chem. 1982, 47, 1024–1027.
7. Nguyen, T. T.; Wilson, S. R.; Martin, J. C. J. Am. Chem. Soc. 1986, 108, 3803–3811.
8. Agosta, W. C. Tetrahedron Lett. 1965, 6, 2681–2685.
100 MHz): d 147.7, 132.0, 123.5, 105.5, 75.5, 29.7; IR (neat)
1420, 1355, 1208, 1154, 944, 885, 856, 803; HRMS (MALDI) m/z calcd for
12H16IO2 [M+H]+: 319.0189, found: 319.0187.
m: 3426, 2967,
C
9. Tian, J.; Gao, W.-C.; Zhou, D.-M.; Zhang, C. Org. Lett. 2012, 14, 3000–3003.
10. Moss, R. A.; Wilk, B.; Jespersen, K. K.; Blair, J. T.; Westbrook, J. D. J. Am. Chem.
Soc. 1989, 111, 250–258.
13. To the solution of compound 10 (160 mg, 0.5 mmol) in anhydrous methanol
(5 mL) was added LiOH (36 mg, 1.5 mmol), and the mixture was stirred at
room temperature for 24 h. After 10 was completely consumed, the solvent
was removed in vacuo, and the solid residue was dissolved in water (5 mL) and
extracted with EtOAc (3 Â 10 mL). The organic layer was dried over anhydrous
Na2SO4, concentrated to give a crude acid product, which was used directly for
the next step. The crude acid was dissolved in chloroform (5 mL), and the
freshly prepared tBuOCl (81 mg, 0.75 mmol) was added dropwise. The resulted
mixture was stirred at room temperature for 3 h, and then the solvent was
removed in vacuo. The crude product was purified by chromatography (PE/
EtOAc, 1:5) to give iodinane 6. Yield: 53%; white solid; mp: 192–194 °C; 1H
NMR (CDCl3, 400 MHz): d 8.18 (d, 1H, J = 7.2 Hz), 7.76 (t, 1H, J = 7.6 Hz), 7.44 (d,
1H, J = 7.6 Hz), 1.60 (s, 6H); 13C NMR (CDCl3, 100 MHz): d 165.2, 146.8, 133.2,
11. To the solution of 8 (1.3 g, 4 mmol) in toluene (10 mL) was added the freshly
prepared Methyl Grignard reagent (20 mL) at 100 °C. After the addition was
complete, the reaction mixture was stirred at reflux for 1 h. And then the
solution of iodine (3 g, 12 mmol) in diethyl ether (15 mL) was added dropwise.
The reaction mixture was stirred at reflux for another 15 min, and quenched
with satd aqueous Na2S2O3 (10 mL) and satd aqueous NaHCO3 (10 mL). The
resulted mixture was extracted with EtOAc (3 Â 20 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was purified by
chromatography (PE/EtOAc, 1:5) to give 9 and 10. Compound 9: 64% yield; pale
yellow solid; mp 142–144 °C; 1H NMR (CDCl3, 400 MHz):
d 7.51 (d, 2H,
J = 8.0 Hz), 7.26 (t, 1H, J = 8.0 Hz), 3.09 (br s, 2H), 1.84 (s, 12H); 13C NMR (CDCl3,
100 MHz): d 149.8, 127.9, 126.4, 94.2, 75.4, 30.9. Compound 10: 22% yield;
colorless oil; 1H NMR (CDCl3, 400 MHz): d 7.62 (dd, 1H, J = 10.0, 1.6 Hz), 7.23 (t,
1H, J = 10.0 Hz), 7.07 (dd, 1H, J = 10.0, 1.6 Hz), 3.83 (s, 3H), 1.67 (s, 6H); 13C
NMR (CDCl3, 100 MHz): d 170.2, 149.8, 142.7, 128.0, 127.9, 126.5, 90.4, 73.9,
52.6, 29.6.
130.1, 129.4, 128.8, 115.2, 85.4, 29.9; IR (neat) m: 3384, 3058, 2966, 1668, 1280,
1249, 1199, 1148, 825, 769; HRMS (MALDI) m/z calcd for C10H10IO3 [M+H]+:
304.9669, found: 304.9665.
14. Macikenas, D.; Skrzypczak-Jankun, E.; Protasiewicz, J. D. J. Am. Chem. Soc. 1999,
121, 7164–7165.
15. Alvarez, S. Dalton Trans. 2013, 42, 8617–8636.