Tethered Silanoxyiodination of Alkenes

Article abstract of DOI:10.1021/acs.joc.1c00872

We present the first examples of tethered silanoxyiodination reactions of allylic alcohols. The products are useful silanediol organoiodide synthons and are formed with high regioselectivity and diastereocontrol. The reaction is scalable greater than 10-fold without loss of yield or selectivity. Furthermore, the products are starting materials for further transformations, including deiodination, C-N bond installation, epoxide synthesis, and desilylation. DFT calculations provide a basis for understanding the exquisite 6-endo selectivity of this silanoxyiodination reaction and show that the observed products are both kinetically and thermodynamically preferred.

Full text of DOI:10.1021/acs.joc.1c00872

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Tethered Silanoxyiodination of Alkenes
Ranjeet A. Dhokale, Frederick J. Seidl, Anand H. Shinde, Joel T. Mague, and Shyam Sathyamoorthi*
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ABSTRACT: We present the first examples of tethered silanoxyiodination
reactions of allylic alcohols. The products are useful silanediol organoiodide
synthons and are formed with high regioselectivity and diastereocontrol. The
reaction is scalable greater than 10-fold without loss of yield or selectivity.
Furthermore, the products are starting materials for further transformations,
including deiodination, C−N bond installation, epoxide synthesis, and desilylation.
DFT calculations provide a basis for understanding the exquisite 6-endo selectivity
of this silanoxyiodination reaction and show that the observed products are both
kinetically and thermodynamically preferred.
ethered alkene functionalization reactions allow the
synthetic chemist to transform olefins with unusual
Scheme 2. Elegant Work with Iodolactonization and
Iodoetherification Inspired This Tethered
Silanoxyiodination
T
precision.1−7 Because of the predisposition for six- and seven-
membered cyclic transition states, one can simply count the
number of atoms from the nucleophilic auxiliary (“the tether”)
where the functionalization event is likely to take place; due to
geometric constraints, these reactions generally proceed with
high regio- and diastereoselectivity. Our laboratory is deeply
invested in developing tethered olefin functionalization
reactions, and we have disclosed such reactions using
sulfamate,8,9 phosphoramidate,10 and di-tert-butylsilanoxy
tethers.11,12
Iodofunctionalization of olefins is a particularly powerful
method for the synthesis of organoiodides, which are versatile
precursors for C−O,13 C−N,14 and C−C bonds15 (Scheme 1).
Scheme 1. Organoiodides Have Proven Versatility
synthons. Here, we describe our efforts to reduce this idea to
practice.
Two particularly well-known classes within this large area are
iodolactonization16−20 and iodoetherification21−24 of olefins
(Scheme 2), and examples of both are found in complex
molecule syntheses. Building on this precedent, we imagined a
silanoxyiodination reaction that would yield protected diol
iodides in a single step and with high regio- and
diastereoselectivity. We reasoned that the di-tert-butyl silyl
group could be facilely removed to reveal useful iodo-diol
Received: April 15, 2021
Published: June 15, 2021
https://doi.org/10.1021/acs.joc.1c00872
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 9233−9243
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Note
Optimization of this tethered silanoxyiodination reaction
began with (E)-di-tert-butyl(hex-2-en-1-yloxy)silanol, conven-
iently prepared in one step from commercially available di-tert-
butylsilyl bis(trifluoromethanesulfonate) and trans-2-hexen-1-
ol.11 With I2 (3 equiv) and NaHCO3 (6 equiv) in acetonitrile
at 0 °C, we were pleased to observe 65% of desired product
(Table 1, entry 1). However, we soon discovered that these
cases proceeds with high regio- and diastereoselectivity. We
have determined the relative configuration of one of these
products through X-ray diffraction analysis, which establishes
that the iodine and the pendant alkyl chain are trans to each
other (Scheme 3, entry 11, CCDC: 2062814). While protocol
A (AgBF4/I2/THF) gave good product yields with several
substrates (Scheme 3, entries 1 and 7), a curious side product
complicated crude NMR analysis and purification. Amazingly,
this side product has been previously characterized and arises
from a ring-opening polymerization of THF by I2!26 We thus
abandoned THF in favor of DME, and we recommend that for
substrates not shown here both protocol B (AgBF4/I2/DME)
and protocol C (AgOTf/I2/DME) should be empirically
tested for best results. We were pleased to find that a variety of
alkyl chains (Scheme 3, entries 1, 2, and 6), rings (Scheme 3,
entries 3 and 4), alkyl ethers (Scheme 3, entry 3), ketals
(Scheme 3, entry 5), esters (Scheme 3, entry 10), aromatic
rings (Scheme 3, entries 8 and 11), and heteroaromatic rings
(Scheme 3, entries 9 and 12) were all tolerated by our
optimized protocols. Furthermore, we were not limited to
disubstituted olefins. A variety of trisubstituted olefins
(Scheme 3, entries 13−15) reacted smoothly as well.
Table 1. Optimization of a Tethered Silanoxyiodination
Reaction
a
b
Ag(I) (equiv)
I2 (equiv)
solvent
temp (°C)
B/A
c
1
2
3
4
5
6
7
8
none
3
MeCN
MeCN
MeCN
MeCN
THF
EtOAc
CH2Cl2
THF
THF
THF
DME
DME
0
0
0
0
0
0
0
−15
−45
−15
−15
65/0
0/0
0/0
58/0
60/0
62/11
22/0
65/0
45/0
70/0
75/0
80/0
d
e
AgNO3 (1)
Ag(TFA) (1)
AgBF4 (1)
AgBF4 (1)
AgBF4 (1)
AgBF4 (1)
AgBF4 (1)
AgBF4 (1)
AgOTf (1)
AgBF4 (1)
AgOTf (1)
1
1
1
1
1
1
1
1
1
1
1
We were pleased to see that the reaction scaled greater than
10-fold without loss of yield or selectivity (Scheme 4).
Furthermore, the cyclic silanediol organoiodide products
were amenable to a variety of further transformations,
including deiodination, nucleophilic azide displacement,
epoxide formation, and silicon removal (Scheme 5).
9
10
11
12
−15
In all cases, we exclusively observed products of 6-endo-trig
cyclization reactions. In order to rationalize such exquisite
selectivity for the 6-endo product over the 5-exo isomer, we
turned to DFT calculations using the ORCA software
package.27,28 All calculations were performed using the
B3LYP functional29,30 with D3BJ dispersion correction31,32
using the RIJCOSX approximation.33 The def2-TZVP basis
set34 was used, and implicit THF solvation was applied using
the SMD model.35 When iodine was present, the def2-ECP36
was applied automatically. Counterions were not modeled for
ionic species. Further details and atomic coordinates are
reported in the Supporting Information.
Upon exposing substrate alkene 1 to molecular iodine, the
immediate product is an intermediate iodonium 61. Intra-
molecular ring closure can proceed via either a 5-exo (62) or a
6-endo (63) transition state, leading to isomeric protonated
products 64 and 65. For the 5-exo pathway, both the transition
state and the cationic product are more than 4 kcal/mol higher
in energy than their 6-endo counterparts (Figure 1). This
overwhelming preference for the 6-endo pathway agrees with
the experimental absence of any 5-exo product, even in trace
amounts. The origin of the 6-endo selectivity is most likely due
to ring strain. For acyclic iodonium 61, the O−Si−O angle is
102.6°, which is 6.9° lower than the ideal tetrahedral angle of
109.5°. This initial acyclic perturbation is likely due to the
presence of the tert-butyl groups on the silicon, a manifestation
of the Thorpe−Ingold effect.37 The 6-endo transition state 63
has an O−Si−O angle of 101.3° and the 6-endo product 65 has
an O−Si−O angle of 97.6°, the latter of which is only 5°
smaller than the acyclic angle on iodonium 61. By contrast, the
5-exo transition state 62 has an O−Si−O angle of 96.7° and
the 5-exo product 64 has an O−Si−O angle of 89.8°, the latter
of which is now geometrically acute and 12.8° smaller than the
acyclic angle on iodonium 61. Thus, the tert-butyl groups on
silicon promote a Si−O−Si angle close to that required for 6-
a
b
Reaction times were between 1 and 2 h in all cases. Yield estimated
from H NMR integration with methyl phenyl sulfone as an internal
standard. With 6 equiv of NaHCO3. Two noncyclized products,
which we presume result from NO3 opening of the iodonium
intermediate. Two noncyclized products, which we presume result
from CF3CO2 opening of the iodonium intermediate.
1
c
d
−
e
−
conditions were much too corrosive with other allylic silanols
and led to markedly reduced product yields. The use of Ag (I)
in conjunction with I2 is well-known for the mild generation of
I+.21,23,25 With AgNO3/I2 (Table 1, entry 2) and with
Ag(TFA)/I2 (Table 1, entry 3) we did not observe any
cyclized product formation. In both cases, we isolated linear
alkyl iodide products, which we presume result from
intermolecular opening of the transient iodonium intermediate
−
−
by NO3 and CF3CO2 . We hypothesized that switching to a
silver salt with a non-nucleophilic counterion would eliminate
intermolecular ring-opening. With AgBF4 in acetonitrile,
tetrahydrofuran, or ethyl acetate (Table 1, entries 4−6) at 0
°C, we observed ∼60% cyclized product formation. Using
CH2Cl2 as a solvent was markedly deleterious (Table 1, entry
7). In THF, when the temperature was reduced from 0 to −15
°C, the yield of cyclized product increased slightly (Table 1,
entry 8); however, dropping the temperature further to −45
°C led to a dramatic decrease in product formation (Table 1,
entry 9). We found that Ag(OTf)/I2 in THF, Ag(OTf)/I2 in
DME, and AgBF4/I2 in DME at −15 °C (Table 1, entries 10−
12) all gave comparable, good yields of cyclized product.
Overall, we chose three protocols (A: AgBF4/I2/THF, B:
AgBF4/I2/DME, C: AgOTf/I2/DME) for further exploration
of scope.
Examination of a variety of allylic silanol substrates (Scheme
3) with these protocols revealed that this transformation is
quite general, tolerant of diverse functional groups, and in most
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Note
Scheme 3. Substrate Scope
endo ring closure, while 5-exo ring closure requires a much
more strained and energetically unfavorable Si−O−Si angle.
In summary, we present the first examples of tethered
silanoxyiodination reactions of allylic alcohols. The products
are useful silanediol organoiodide synthons and are formed
with high regioselectivity and diastereocontrol. The reaction is
scalable greater than 10-fold without loss of yield or selectivity.
Furthermore, the products are starting materials for further
Scheme 4. Silanoxyiodination Scales Greater than 10-Fold
without Loss of Yield or Selectivity
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Note
and 100 MHz. 1H NMR spectra were recorded at 400 MHz. Data are
recorded as chemical shift in ppm referenced internally using residue
solvent peaks, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet or overlap of nonequivalent resonances),
integration, and coupling constant (Hz). 13C NMR spectra were
recorded at 100 MHz. Exact mass spectra were recorded using an
electrospray ion source (ESI) either in positive mode or negative
mode with a time-of-flight (TOF) analyzer on a Waters LCT
PremierTM mass spectrometer and are given in m/z. TLC was
performed on precoated glass plates (Merck) and visualized either
with a UV lamp (254 nm) or by dipping into a solution of KMnO4−
K2CO3 in water followed by heating. Flash chromatography was
performed on silica gel (230−400 mesh) or Florisil (60−100 mesh).
II. Characterization of Previously Unreported Substrates.
Note 1: Substrates were synthesized according to previously reported
procedures.11 Note 2: Compounds 1−4, 6−8, 11, 13−17, 19, 20, 23,
Scheme 5. Products Are Versatile Synthons for (A)
Deiodination, (B) C−N Bond Formation, (C) Epoxide
Formation, and (D) Silicon Removal
and 25 have been reported previously.11,12
.
(E)-Di-tert-butyl((6-methylhept-2-en-1-yl)oxy)silanol (5). Purified
using a gradient of 0−10% EtOAc in hexanes on silica gel (yellow oil,
1
476 mg, 83%); H NMR (400 MHz, chloroform-d) δ 5.69 (ddt, J =
14.1, 6.2, 1.2 Hz, 1H), 5.59 (dtt, J = 15.3, 5.3, 1.2 Hz, 1H), 4.35−4.28
(m, 2H), 2.12−2.01 (m, 2H), 1.58 (dq, J = 13.3, 6.7 Hz, 1H), 1.33−
1.24 (m, 2H), 1.05 (s, 18H), 0.91 (d, J = 6.6 Hz, 6H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 131.6, 129.1, 64.2, 38.4, 30.0, 27.5, 27.42,
22.47, 20.46; IR 2857, 1457, 1173 cm−1; HRMS (ESI) calcd for
C16H33O2Si− 285.2250, found 285.2245 (M−).
(E)-Di-tert-butyl((3-(tetrahydro-2H-pyran-4-yl)allyl)oxy)silanol
(9). Purified using a gradient of 0 to 50% acetone/DCM; (light yellow
1
oil, 403 mg, 67% yield); H NMR (400 MHz, CDCl3) δ 5.63−5.54
(m, 1H), 5.54−5.42 (m, 1H), 4.24 (tt, J = 4.8, 1.2 Hz, 2H), 3.89 (ddt,
J = 12.5, 4.2, 1.6 Hz, 2H), 3.35 (tt, J = 11.6, 2.2 Hz, 2H), 2.20−2.12
(m, 1H), 1.55 (ddq, J = 12.8, 4.1, 2.0 Hz, 2H), 1.46−1.30 (m, 2H),
0.95 (s, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 134.8, 134.4,
127.9, 127.6, 67.7, 64.1, 63.9, 37.3, 32.6, 32.5, 27.8, 27.4, 21.2, 20.4;
IR 2933, 1473, 1127, 827, 648 cm−1; HRMS (ESI) calcd for
C16H31O3Si− 299.2048, found 299.2055 (M−).
Figure 1. DFT energies for cationic iodonium rearrangements of
substrate 1.
tert-Butyl (E)-4-(3-((di-tert-butyl(hydroxy)silyl)oxy)prop-1-en-1-
yl)piperidine-1-carboxylate (10). Purified using a gradient of 0−
1
10% EtOAc in hexanes on silica gel (colorless oil, 663 mg, 83%); H
transformations, including deiodination, C−N bond installa-
tion, epoxide synthesis, and desilylation. DFT calculations
provide a basis for understanding the exquisite 6-endo
selectivity of this silanoxyiodination reaction. We expect this
reaction to find much use in the construction of complex
molecules containing functional group stereochemical arrays.
NMR (400 MHz, chloroform-d) δ 5.70−5.55 (m, 2H), 4.33 (dd, J =
4.8, 1.2 Hz, 2H), 4.11 (dt, J = 13.7, 3.6 Hz, 2H), 2.76 (ddd, J = 13.3,
12.2, 2.8 Hz, 2H), 2.14 (td, J = 10.8, 5.9 Hz, 1H), 1.74−1.65 (m, 2H),
1.48 (s, 9H), 1.37−1.25 (m, 2H), 1.05 (s, 18H); 13C{1H} NMR (101
MHz, chloroform-d) δ 154.9, 134.6, 128.0, 79.3, 63.9, 43.6, 38.4, 31.7,
28.4, 27.4, 20.4; IR 2857, 1457, 1173 cm−1; HRMS (ESI) calcd for
C21H41NO4SiNa+ 422.2703, found mass 422.2692 (MNa+).
EXPERIMENTAL SECTION
■
I. General Considerations. All reagents were obtained
commercially unless otherwise noted. Solvents were purified by
passage under 10 psi N2 through activated alumina columns. Infrared
(IR) spectra were recorded on a Thermo Scientific Nicolet iS5 FT-IR
spectrometer; data are reported in frequency of absorption (cm−1).
NMR spectra were recorded on a Bruker Avance 400 operating at 400
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(S,E)-((3-(1,4-Dioxaspiro[4.5]decan-2-yl)allyl)oxy)di-tert-butylsi-
lanol (12). Purified using a gradient of 0−20% EtOAc/hexanes
1
(colorless oil, 420 mg, 59% yield); H NMR (400 MHz, CDCl3) δ
5.92 (dtd, J = 15.3, 4.5, 0.9 Hz, 1H), 5.75 (ddt, J = 15.4, 7.4, 1.7 Hz,
1H), 4.62−4.50 (m, 1H), 4.39 (ddd, J = 4.5, 1.7, 0.7 Hz, 2H), 4.14−
4.09 (m, 1H), 3.68−3.53 (m, 1H), 1.72−1.58 (m, 9H), 1.43 (m, 1H),
1.05 (s, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 133.4, 127.4,
109.8, 76.2, 69.1, 63.0, 36.2, 35.4, 27.4, 25.1, 23.9, 23.8, 20.5; IR 2866,
1465, 1082, 829 cm−1; HRMS (ESI) calcd for C19H35O4Si− 355.2310,
found 355.2336 (M−).
Di-tert-butyl((3-ethylpent-2-en-1-yl)oxy)silanol (26). Purified
using a gradient of 0−10% EtOAc in hexanes on silica gel (colorless
oil, 409 mg, 75%); 1H NMR (400 MHz, chloroform-d) δ 5.32 (td, J =
6.5, 3.3 Hz, 1H), 4.40 (dd, J = 6.3, 1.2 Hz, 2H), 2.13−2.01 (m, 4H),
1.08−0.97 (m, 6H),1.05 (s, 18H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 144.6, 122.7, 60.1, 28.9, 27.4, 23.6, 20.4, 13.3, 12.5;
IR 2933, 1471, 1107 cm−1; HRMS (ESI) calcd for C15H31O2Si−
271.2093 found 271.2091 (M−).
(E)-((3-(4-Bromophenyl)allyl)oxy)di-tert-butylsilanol (18). Puri-
fied using a gradient of 0−0.2% acetone in DCM (light yellow oil,
1
319 mg, 43% yield); H NMR (400 MHz, CDCl3) δ 7.57−7.40 (m,
2H), 7.40−7.16 (m, 2H), 6.61 (dt, J = 15.9, 2.0 Hz, 1H), 6.33 (dt, J =
15.8, 4.9 Hz, 1H), 4.55 (dd, J = 4.9, 1.8 Hz, 2H), 1.09 (d, J = 0.9 Hz,
18H); 13C{1H} NMR (101 MHz, CDCl3) δ 136.2, 131.7, 130.1,
128.2, 128.0, 121.1, 63.9, 27.5, 20.6; IR 3471, 2919, 1479, 1378, 829
cm−1; HRMS (ESI) calcd for C17H26BrO2Si− 369.0891, found
369.0867 (M−).
(E)-Di-tert-butyl((3,7,11,15-tetramethylhexadec-2-en-1-yl)oxy)-
silanol (27). Purified using a gradient of 0−0.1% acetone in DCM
1
(colorless oil, 400 mg, 44% yield); H NMR (400 MHz, CDCl3) δ
5.37 (tq, J = 6.3, 1.3 Hz, 1H), 4.39 (dq, J = 6.4, 0.9 Hz, 2H), 2.05−
1.96 (m, 2H), 1.65 (t, J = 0.8 Hz, 3H), 1.56 (dp, J = 13.3, 6.6 Hz,
1H), 1.49−1.08 (m, 18H), 1.05 (s, 18H), 0.89 (ddd, J = 8.5, 6.6, 0.7
Hz, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ 137.4, 124.3, 60.4,
39.8, 39.3, 37.4, 37.4, 37.3, 36.6, 32.8, 32.7, 27.9, 27.4, 25.1, 24.8,
24.4, 22.7, 22.6, 20.4, 19.7, 19.7, 16.2; IR 2928, 1471, 1364, 1099, 827
cm−1; HRMS (ESI) calcd for C28H58NaO2Si+ 477.4098, found
477.4067 (MNa+).
(E)-4-((Di-tert-butyl(hydroxy)silyl)oxy)but-2-en-1-yl acetate (21).
Purified using a gradient of 0−50% acetone in DCM on silica gel
followed by a gradient of 0 to 100% acetonitrile in 0.1%TFA/H2O on
a RediSep Prep C18 column (100 Å, 5 μm, Length 250 mm i.d.: 20
mm, flow rate of 15 mL/min) (light yellow oil, 288 mg, 50% yield);
1H NMR (400 MHz, CDCl3) δ 5.96−5.78 (m, 2H), 4.67−4.56 (m,
2H), 4.40 (dt, J = 4.0, 1.3 Hz, 2H), 2.10 (s, 3H), 1.06 (s, 18H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 134.2, 123.3, 64.6, 63.0,
27.4, 20.9, 20.5; IR 3442, 2947, 1730, 1246, 829 cm−1; HRMS (ESI)
calcd for C14H27O4Si− 287.1684, found 287.1661 (M−).
Di-tert-butyl(2-(tetrahydro-4H-pyran-4-ylidene)ethoxy)silanol
(28). Purified using a gradient of 0−10% EtOAc in hexanes on silica
gel (colorless oil, 401 mg, 70%); 1H NMR (400 MHz, chloroform-d)
δ 5.44 (tt, J = 6.6, 1.3 Hz, 1H), 4.39 (d, J = 6.5 Hz, 2H), 3.71 (dt, J =
13.3, 5.5 Hz, 4H), 2.36−2.29 (m, 2H), 2.29−2.22 (m, 2H), 1.98 (s,
1H), 1.05 (s, 18H); 13C{1H} NMR (101 MHz, chloroform-d) δ
136.3, 123.1, 69.4, 68.5, 59.1, 36.6, 29.9, 27.3, 20.4; IR 2933, 1471,
1107 cm−1; HRMS (ESI) calcd for C15H30O3SiNa+ 309.1856 found
309.1821 (MNa+).
(E)-4-((Di-tert-butyl(hydroxy)silyl)oxy)but-2-en-1-yl benzoate
(22). Purified using a gradient of 0−50% acetone/DCM on silica
gel (light yellow semisolid, 343 mg, 49% yield); 1H NMR (400 MHz,
CDCl3) δ 8.09−7.98 (m, 2H), 7.60−7.53 (m, 1H), 7.44 (ddd, J = 8.2,
6.7, 1.2 Hz, 2H), 6.03−5.88 (m, 2H), 4.83 (tt, J = 2.3, 1.3 Hz, 2H),
4.40 (p, J = 1.4 Hz, 2H), 1.03 (s, 18H). 13C{1H} NMR (101 MHz,
CDCl3) δ 166.6, 134.2, 133.0, 130.3, 129.7, 128.4, 123.7, 65.0, 63.2,
27.5, 20.6; IR 3447, 2933, 1704, 1279, 827 cm−1; HRMS (ESI) calcd
for C19H29O4Si− 349.1841, found 349.1813 (M−).
III. General Protocols for Silanoxyiodination of Alkenes.
Protocol A. A microwave vial was charged with stir bar, alkene
substrate (0.2 mmol, 1 equiv), AgBF4 (39 mg, 0.2 mmol, 1 equiv),
and 2 mL of anhydrous THF. The reaction vial was immersed in a
bath set to −15 °C. I2 (51 mg, 0.2 mmol, 1 equiv) was added in one
portion. A light yellow precipitate formed immediately upon addition
of AgBF4. The heterogeneous mixture was stirred for 1 h at −15 °C
and then quenched by addition of aqueous saturated Na2S2O3. The
reaction mixture was diluted with ethyl acetate and transferred to a
separatory funnel. The organic portion was collected, and the aqueous
layer was extracted with two additional portions of ethyl acetate. The
organic fractions were pooled, dried with MgSO4, and concentrated
under reduced pressure. The resulting residue was purified by
chromatography on Florisil (specific conditions are associated with
each compound).
(E)-Di-tert-butyl((3-(pyridin-3-yl)allyl)oxy)silanol (24). Purified
using a gradient of 0−10% EtOAc in hexanes on silica gel (colorless
oil, 411 mg, 70%); 1H NMR (400 MHz, chloroform-d) δ 8.60 (d, J =
2.2 Hz, 1H), 8.47 (dd, J = 4.9, 1.6 Hz, 1H), 7.71 (dt, J = 7.9, 1.9 Hz,
1H), 7.27 (dd, J = 7.9, 4.9 Hz, 1H), 6.65 (dd, J = 15.9, 1.8 Hz, 1H),
6.40 (ddd, J = 16.0, 5.1, 4.2 Hz, 1H), 4.58 (dd, J = 4.7, 1.9 Hz, 2H),
1.10 (s, 18H); 13C{1H} NMR (101 MHz, chloroform-d) δ 148.0,
147.9, 133.0, 132.9, 131.9, 125.3, 123.5, 63.6, 27.4, 20.5; IR 2856,
1471, 1134 cm−1; HRMS (ESI) calcd for C16H28NO2Si+ 294.1884
found 294.1852 (MH+).
Protocol B. A microwave vial was charged with stir bar, alkene
substrate (0.2 mmol, 1 equiv), AgBF4 (39 mg, 0.2 mmol, 1 equiv),
and 2 mL of anhydrous DME. The reaction vial was immersed in a
bath set to −15 °C. I2 (51 mg, 0.2 mmol, 1 equiv) was added in one
portion. A light-yellow precipitate formed immediately upon addition
of AgBF4. The heterogeneous mixture was stirred for 1 h at −15 °C
and then quenched by addition of aqueous saturated Na2S2O3. The
reaction mixture was diluted with ethyl acetate and transferred to a
separatory funnel. The organic portion was collected, and the aqueous
layer was extracted with two additional portions of ethyl acetate. The
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Note
organic fractions were pooled, dried with MgSO4, and concentrated
under reduced pressure. The resulting residue was purified by
chromatography on Florisil (specific conditions are associated with
each compound).
2.00−1.84 (m, 2H), 1.44−1.37 (m, 1H), 1.05 (s, 9H), 0.99 (s, 9H),
0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 77.2, 71.2, 46.8, 34.1, 27.4, 26.9, 24.3,
23.7, 22.8, 21.1, 19.8; IR 2957, 1364, 903 cm−1; HRMS (ESI) calcd
for C15H32IO2Si+ 399.1216, found 399.1253 (MH+).
Protocol C. A microwave vial was charged with stir bar, alkene
substrate (0.2 mmol, 1 equiv), AgOTf (51 mg, 0.2 mmol, 1 equiv),
and 2 mL of anhydrous DME. The reaction vial was immersed in a
bath set to −15 °C. I2 (51 mg, 0.2 mmol, 1 equiv) was added in one
portion. A light-yellow precipitate formed immediately upon addition
of AgOTf. The heterogeneous mixture was stirred for 1 h at −15 °C
and then quenched by addition of aqueous saturated Na2S2O3. The
reaction mixture was diluted with ethyl acetate and transferred to a
separatory funnel. The organic portion was collected, and the aqueous
layer was extracted with two additional portions of ethyl acetate. The
organic fractions were pooled, dried with MgSO4, and concentrated
under reduced pressure. The resulting residue was purified by
chromatography on Florisil (specific conditions are associated with
each compound).
2,2-Di-tert-butyl-5-iodo-4-isopentyl-1,3,2-dioxasilinane (33).
Synthesized using protocol B; purified using 100% benzene on
1
Florisil; single diastereomer (colorless oil, 73 mg, 89%); H NMR
(400 MHz, chloroform-d) δ 4.29−4.02 (m, 4H), 2.14−2.04 (m, 1H),
1.63−1.46 (m, 2H), 1.43−1.26 (m, 2H), 1.05 (s, 9H), 1.00 (s, 9H),
0.93 (d, J = 4.9 Hz, 3H), 0.91 (d, J = 4.8 Hz, 3H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 78.7, 71.2, 35.4, 33.6, 33.3, 27.6, 27.4,
26.9, 23.0, 22.8, 22.2, 19.9; IR 2956, 1137, 896 cm−1; HRMS (ESI)
calcd for C16H34IO2Si+ 413.1373, found 413.1370 (MH+).
IV. Characterization of Iodinated Products.
2,2-Di-tert-butyl-5-iodo-4-methyl-1,3,2-dioxasilinane (29). Synthe-
sized using protocol C; single diastereomer; purified using benzene on
Florisil (light yellow semisolid, 66 mg, 92% isolated yield); H NMR
(400 MHz, CDCl3) δ 4.31 (dq, J = 10.2, 6.0 Hz, 1H), 4.27−4.16 (m,
2H), 4.01 (td, J = 10.5, 5.2 Hz, 1H), 1.53 (d, J = 6.0 Hz, 3H), 1.07 (s,
9H), 1.01 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 75.7, 71.0,
34.2, 27.4, 26.9, 24.8, 22.7, 19.8; IR 2960, 1474, 1136, 825 cm−1;
HRMS (ESI) calcd for C12H26IO2Si+ 357.0741, found 357.0740
(MH+).
2,2-Di-tert-butyl-5-iodo-4-isopropyl-1,3,2-dioxasilinane (34).
Synthesized using protocol B; purified using benzene on Florisil
(light yellow semisolid, 45 mg, 58% isolated yield); single
1
1
diastereomer; H NMR (400 MHz, CDCl3) δ 4.32 (dd, J = 10.4,
4.2 Hz, 1H), 4.24 (t, J = 10.7 Hz, 1H), 4.21−4.12 (m, 1H), 4.02 (dd,
J = 10.1, 2.0 Hz, 1H), 2.34 (pd, J = 6.8, 2.0 Hz, 1H), 1.07 (s, 9H),
1.04 (d, J = 6.4 Hz, 12H), 0.87 (d, J = 6.7 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 81.7, 71.8, 33.0, 31.8, 27.6, 26.9, 23.0, 20.2,
20.0, 13.2; IR 2960, 1076, 1028, 764 cm−1; HRMS (ESI) calcd for
C14H30IO2Si+ 385.1060, found 385.1052 (MH+).
2,2-Di-tert-butyl-5-iodo-4-propyl-1,3,2-dioxasilinane (30). Syn-
thesized using protocol A; single diastereomer; light yellow solid;
purified using a gradient of 0−10% EtOAc in hexanes on silica gel; 54
1
mg, 70% isolated yield; H NMR (400 MHz, CDCl3) δ 4.20−4.09
( ) 4-sec-Butyl-2,2-di-tert-butyl-5-iodo-1,3,2-dioxasilinane (35).
Synthesized using protocol B; purified using 100% benzene on
Florisil; ∼1:1 mixture of diastereomers (colorless oil, 38 mg, 48%);
1H NMR (400 MHz, chloroform-d) δ 4.36−4.27 (m, 1H), 4.27−4.14
(m, 2H), 4.08−4.00 (m, 1H), 2.07 (dddd, J = 18.4, 8.8, 5.1, 1.9 Hz,
1H), 1.56−1.46 (m, 1H), 1.46−1.34 (m, 1H), 1.24−1.14 (m, 1H),
1.07 (s, 4H), 1.06 (s, 5H), 1.04 (s, 1H), 1.03 (s, 4H), 1.02 (s, 5H),
0.97 (m, 3H), 0.87 (d, J = 6.7 Hz, 1H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 82.6, 79.8, 71.9, 71.8, 39.8, 39.7, 31.6, 31.5, 27.6,
27.5, 27.0, 26.9, 26.8, 23.0, 20.4, 20.2, 16.5, 12.0, 11.7, 11.4; IR 2859,
1474, 939 cm−1; HRMS (ESI) calcd for C15H32IO2Si+ 399.1216,
found 399.1161 (MH+).
(m, 2H), 4.05 (ddd, J = 10.2, 8.0, 2.2 Hz, 1H), 3.98 (td, J = 10.4, 4.9
Hz, 1H), 2.02−1.91 (m, 1H), 1.52−1.32 (m, 3H), 0.97 (s, 9H), 0.91
(s, 9H), 0.88 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 78.3, 71.3, 39.8, 33.2, 27.4, 26.9, 22.8, 19.9, 17.9, 13.7; IR 2960,
1474, 1135, 825 cm−1; HRMS (ESI) calcd for C14H30IO2Si+
385.1054, found 385.1057 (MH+).
2,2-Di-tert-butyl-5-iodo-4-nonyl-1,3,2-dioxasilinane (31). Syn-
thesized using protocol A; single diastereomer; purified using benzene
1
on Florisil (colorless oil, 64 mg, 68% isolated yield); H NMR (400
MHz, CDCl3) δ 4.20−4.08 (m, 2H), 4.08−3.93 (m, 2H), 2.04−1.92
(m, 1H), 1.50−1.14 (m, 15H), 0.97 (s, 9H), 0.92 (s, 9H), 0.85−0.77
(m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 78.5, 71.3, 37.6, 33.3,
31.9, 29.5, 29.3, 29.1, 27.4, 26.9, 24.5, 22.8, 22.7, 19.9, 14.1; IR 2927,
1473, 1133, 825 cm−1; HRMS (ESI) calcd for C20H42IO2Si+
469.1993, found 469.1993 (MH+).
2,2-Di-tert-butyl-4-cyclohexyl-5-iodo-1,3,2-dioxasilinane (36).
Synthesized using protocol B; purified using benzene on Florisil
(colorless semisolid, 59 mg, 70% isolated yield); single diastereomer;
1H NMR (400 MHz, CDCl3) δ 4.34−4.17 (m, 3H), 3.98 (dt, J = 8.1,
2.1 Hz, 1H), 2.00 (td, J = 5.3, 2.5 Hz, 1H), 1.86−1.74 (m, 2H), 1.70
(dt, J = 12.6, 2.8 Hz, 1H), 1.59 (dd, J = 8.4, 3.2 Hz, 1H), 1.53 (td, J =
9.4, 3.4 Hz, 2H), 1.40−1.12 (m, 4H), 1.06 (s, 9H), 1.03 (s, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 81.6, 71.8, 43.5, 31.1, 30.2, 27.6,
27.0, 26.5, 26.4, 26.0, 23.8, 23.0, 20.2; IR 2930, 1072, 1001, 975 cm−1;
HRMS (ESI) calcd for C17H34IO2Si+ 425.1367, found 425.1358
(MH+).
( )-2,2-Di-tert-butyl-5-iodo-4-isobutyl-1,3,2-dioxasilinane (32).
Synthesized using protocol B; single diastereomer; purified using
100% benzene on Florisil (colorless oil, 52 mg, 65%); 1H NMR (400
MHz, chloroform-d) δ 4.28−4.12 (m, 3H), 3.97−4.05 (m, 1H),
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Note
2,2-Di-tert-butyl-5-iodo-4-(tetrahydro-2H-pyran-4-yl)-1,3,2diox-
asilinane (37). Synthesized using protocol B; purified using a gradient
of 0−40% EtOAc/benzene on Florisil; single diastereomer (light
yellow oil, 64 mg, 75% isolated yield); 1H NMR (400 MHz, CDCl3) δ
4.23 (dd, J = 10.1, 3.9 Hz, 1H), 4.19−4.03 (m, 2H), 4.01−3.90 (m,
3H), 3.43−3.27 (m, 2H), 2.17 (ttd, J = 11.8, 3.7, 2.0 Hz, 1H), 1.92−
1.79 (m, 1H), 1.66−1.52 (m, 1H), 1.32 (dddt, J = 13.3, 11.5, 3.8, 2.1
Hz, 2H), 0.98 (s, 9H), 0.93 (s, 9H). 13C{1H} NMR (101 MHz,
CDCl3) δ 80.5, 71.6, 68.0, 67.7, 40.5, 30.1, 29.5, 27.6, 26.9, 23.9, 23.0,
20.2; IR 2857, 1163, 1080, 825 cm−1; HRMS (ESI) calcd for
C16H32IO3Si+ 427.1166, found 427.1162 (MH+).
2,2-Di-tert-butyl-4-(2,6-dimethylheptyl)-5-iodo-1,3,2-dioxasili-
nane (41). Synthesized using protocol C; purified using 100%
benzene on Florisil; ∼1:1 mixture of diastereomers (colorless oil, 61
mg, 65%); 1H NMR (400 MHz, chloroform-d) δ 4.29−4.15 (m, 3H),
4.06−3.99 (m, 1H), 2.03 (ddd, J = 13.6, 8.9, 2.1 Hz, 1.4H), 1.87−
1.76 (m, 0.6H), 1.60−1.50 (m, 1H), 1.47−1.37 (m, 1H), 1.37−1.31
(m, 1H), 1.30−1.22 (m, 2H), 1.20−1.13 (m, 2H), 1.12−1.07 (m,
1H), 1.05 (s, 9H), 0.99 (s, 9H), 0.95 (d, J = 6.8 Hz, 1.8H), 0.92 (d, J
= 6.2 Hz, 1.2H), 0.89 (d, J = 1.2 Hz, 3H), 0.87 (d, J = 1.0 Hz, 3H);
13C{1H} NMR (101 MHz, chloroform-d) δ 71.2, 71.2, 45.2, 44.7,
39.3, 39.1, 37.9, 35.6, 34.3, 29.3, 28.7, 27.9, 27.9, 27.44, 27.42, 26.9,
24.7, 24.4, 22.84, 22.81, 22.74, 22.70, 22.66, 22.59, 20.7, 19.8, 19.0; IR
2859, 1474, 906 cm−1; HRMS (ESI) calcd for C20H42IO2Si+
469.1999, found 469.2005 (MH+).
2,2-Di-tert-butyl-5-iodo-1,3,2-dioxasilinan-4-yl)piperidine-1-car-
boxylate (38). Synthesized using protocol B; purified using 100%
benzene on Florisil; single diastereomer (colorless oil, 51 mg, 48%);
1H NMR (400 MHz, chloroform-d) δ 4.32−4.10 (m, 5H), 4.02 (dd, J
= 10.1, 2.0 Hz, 1H), 2.70 (dd, J = 25.1, 13.4 Hz, 2H), 2.12 (ddddd, J
= 13.6, 11.6, 9.7, 4.9, 2.0 Hz, 1H), 1.68 (dd, J = 28.2, 13.7 Hz, 1H),
1.52−1.45 (m, 3H), 1.47 (s, 9H), 1.03 (s, 9H), 0.98 (s, 9H); 13C{1H}
NMR (101 MHz, chloroform-d) δ 154.9, 80.5, 79.3, 71.6, 43.9, 41.4,
30.3, 28.4, 27.5, 26.9, 23.0, 22.9, 20.1; IR 2933, 1423, 923 cm−1;
HRMS (ESI) calcd for C21H41INO4Si+ 526.1850, found 526.1891
(MH+).
2,2-Di-tert-butyl-4-ethyl-5-iodo-1,3,2-dioxasilinane-6-d (42).
Synthesized using protocol A; purified using benzene on Florisil
followed by eluting with 20% EtOAc/hexanes on a small plug of silica
gel; mixture of diastereomers; (light yellow semisolid, 46 mg, 62%
1
isolated yield); H NMR (400 MHz, CDCl3) δ 4.18−4.05 (m, 1H),
4.04−3.94 (m, 2H), 2.03 (dqd, J = 14.8, 7.4, 1.8 Hz, 1H), 1.58−1.42
(m, 1H), 0.97 (s, 9H), 0.91 (d, J = 7.1 Hz, 12H); 13C{1H} NMR (101
MHz, CDCl3) δ 79.5, 71.1−70.5 (m), 32.5, 30.6, 27.4, 26.9, 22.8,
19.9, 8.8; IR 2961, 1473, 1135, 827 cm−1; HRMS (ESI) calcd for
C13H27DIO2Si+ 372.0961, found 372.0959 (MH+).
2,2-Di-tert-butyl-5-iodo-4-methylcyclohexyl)-1,3,2-dioxasilinane
(39). Synthesized using protocol B; purified using benzene on Florisil;
single diastereomer (colorless oil, 63 mg, 72% yield); H NMR (400
2,2-Di-tert-butyl-4-hexyl-5-iodo-1,3,2-dioxasilinane-6-d (43).
Synthesized using protocol B; purified using benzene on Florisil;
mixture of diastereomers (light yellow semisolid, 57 mg, 67% isolated
1
MHz, CDCl3) δ 4.24−4.09 (m, 3H), 3.91 (dt, J = 8.8, 2.0 Hz, 1H),
1.88−1.78 (m, 1H), 1.67 (ddt, J = 13.6, 5.9, 1.9 Hz, 2H), 1.54−1.40
(m, 3H), 1.19 (dtt, J = 12.2, 9.0, 5.6 Hz, 3H), 0.96 (s, 9H), 0.92 (s,
9H), 0.94−0.84 (m, 1H), 0.81 (d, J = 6.5 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 81.3, 71.8, 42.5, 35.0, 34.6, 32.7, 31.3, 30.0,
27.6, 27.0, 23.5, 23.0, 22.6, 20.2; IR 2928, 1455, 1117, 825 cm−1;
HRMS (ESI) calcd for C18H36IO2Si+ 439.1524, found 439.1516
(MH+).
1
yield); H NMR (400 MHz, CDCl3) δ 4.25−4.15 (m, 1H), 4.11
(ddd, J = 10.2, 7.8, 2.3 Hz, 1H), 4.08−4.00 (m, 1H), 2.13−1.99 (m,
1H), 1.57−1.45 (m, 2H), 1.38−1.19 (m, 7H), 1.04 (s, 9H), 0.99 (s,
9H), 0.92−0.87 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 78.7,
71.3−70.7 (m), 37.7, 33.3, 31.9, 29.0, 27.6, 27.0, 24.6, 23.0, 22.7, 20.0,
14.2; IR 2957, 1473, 1088, 827 cm−1; HRMS (ESI) calcd for
C17H35DIO2Si+ 428.1587, found 428.1578 (MH+).
2,2-Di-tert-butyl-5-iodo-4-phenyl-1,3,2-dioxasilinane (44). Syn-
thesized using protocol C; purified using 100% benzene on Florisil;
single diastereomer (colorless oil, 66 mg, 79%); 1H NMR (400 MHz,
chloroform-d) δ 7.48−7.35 (m, 5H), 5.13 (d, J = 9.8 Hz, 1H), 4.48−
4.30 (m, 3H), 1.14 (s, 18H); 13C{1H} NMR (101 MHz, chloroform-
d) δ 142.4, 128.4, 128.1, 127.3, 82.0, 71.6, 34.2, 27.5, 27.0, 23.0, 20.2;
2,2-Di-tert-butyl-5-iodo-4-((R)-1,4 dioxaspiro[4.5]decan-2-yl)-
1,3,2-dioxasilinane (40). Synthesized using protocol B; purified
using a gradient of 0 to 5% EtOAc/hexanes on Florisil; single
1
diastereomer (colorless oil, 34 mg, 35% yield); H NMR (400 MHz,
IR 2859, 1471, 903 cm− 1
C17H27IO2SiNa+441.0717, found 441.0669 (MNa+).
; HRMS (ESI) calcd for
CDCl3) δ 4.45 (td, J = 6.7, 3.6 Hz, 1H), 4.30 (dd, J = 10.7, 3.6 Hz,
1H), 4.22−4.10 (m, 2H), 4.00−3.92 (m, 2H), 3.81 (td, J = 10.6, 5.2
Hz, 1H), 1.72−1.61 (m, 1H), 1.61−1.46 (m, 7H), 1.33 (s, 2H), 0.99
(s, 9H), 0.93 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 110.3,
79.2, 77.5, 71.6, 63.7, 35.7, 35.6, 27.5, 26.9, 26.4, 25.2, 24.0, 23.8,
23.0, 20.1; IR 2933, 1110, 1058, 825 cm−1; HRMS calculated for
C19H36IO4Si+ 483.1422, found 483.1414 (MH+).
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Note
2,2-Di-tert-butyl-4-(4-fluorophenyl)-5-iodo-1,3,2-dioxasilinane
(45). Synthesized using protocol B; purified using 100% benzene on
Florisil; single diastereomer (colorless oil, 61 mg, 70%); H NMR
34.4, 27.5, 27.4, 20.9, 20.7, 20.5; IR 3442, 2947, 1730, 1246, 829 cm
−1; HRMS (ESI) calcd for C14H28IO4Si+ 415.0796, found 415.0788
(MH+).
1
(400 MHz, chloroform-d) δ 7.46−7.35 (m, 2H), 7.14−7.03 (m, 2H),
5.11 (d, J = 10.3 Hz, 1H), 4.47−4.24 (m, 3H), 1.13 (s, 9H), 1.12 (s,
9H); 13C{1H} NMR (101 MHz, chloroform-d) δ 162.6 (d, J = 246.7
Hz), 138.4, 128.9 (d, J = 8.1 Hz), 115.0 (d, J = 21.3 Hz), 81.2, 71.5,
34.2, 27.5, 27.0, 23.0, 20.1; IR 2859, 1471, 1009 cm−1; HRMS (ESI)
calcd for C17H27FIO2Si+ 437.0809, found 437.0796 (MH+).
2,2-Di-tert-butyl-5-iodo-1,3,2-dioxasilinan-4-yl)methyl Benzoate
(50). Synthesized using protocol B; purified using a gradient of 0−
50% acetone/DCM on Florisil followed by preparative TLC; single
1
diastereomer (light yellow oil, 34 mg, 36% yield); H NMR (400
MHz, CDCl3) δ 8.10−7.99 (m, 2H), 7.62−7.54 (m, 1H), 7.49−7.40
(m, 2H), 4.78 (dd, J = 11.9, 2.7 Hz, 1H), 4.54 (dd, J = 11.9, 5.8 Hz,
1H), 4.38 (dd, J = 11.4, 3.7 Hz, 1H), 4.28 (ddd, J = 7.4, 5.7, 3.7 Hz,
1H), 4.19 (ddd, J = 7.4, 5.8, 2.7 Hz, 1H), 4.14 (dd, J = 11.3, 5.7 Hz,
1H), 1.05 (s, 9H), 1.04 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
167.1, 133.5, 129.9, 129.7, 128.6, 71.8, 68.5, 66.3, 34.8, 27.6, 27.5,
20.8, 20.6; IR 3447, 2933, 1704, 1279, 827 cm−1; HRMS (ESI) calcd
for C19H30IO4Si+477.0953, found 477.0985 (MH+).
4-(4-Bromophenyl)-2,2-di-tert-butyl-5-iodo-1,3,2-dioxasilinane
(46). Synthesized using protocol B; purified using benzene on Florisil;
1
single diastereomer (colorless oil, 79 mg, 80% yield); H NMR (400
MHz, CDCl3) δ 7.47−7.33 (m, 2H), 7.22−7.12 (m, 2H), 4.94 (d, J =
10.3 Hz, 1H), 4.34−4.21 (m, 2H), 4.13 (td, J = 10.4, 5.3 Hz, 1H),
0.99 (s, 9H), 0.98 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
141.4, 131.3, 129.0, 122.3, 81.4, 71.5, 33.6, 27.5, 27.0, 23.0, 20.2; IR
2944, 1475, 1110, 827 cm−1; HRMS (ESI) calcd for C17H27BrIO2Si+
497.0003, found 496.9971 (MH+).
2,2-Di-tert-butyl-5-iodo-4-phenethyl-1,3,2-dioxasilinane (51).
Synthesized using protocol B; purified using a gradient of 0−10%
EtOAc in hexanes on silica gel; single diastereomer (light yellow solid,
1
4-(2,2-di-tert-butyl-5-iodo-1,3,2-dioxasilinan-4-yl)phenyl)-
morpholine (47). Synthesized using protocol C; purified using 100%
benzene on Florisil; single diastereomer (colorless oil, 50 mg, 50%);
1H NMR (400 MHz, chloroform-d) δ 7.34 (d, J = 8.8 Hz, 2H), 6.94
(d, J = 8.2 Hz, 2H), 5.10−4.97 (m, 1H), 4.47−4.31 (m, 3H), 3.95−
3.85 (m, 4H), 3.22 (dd, J = 5.8, 3.9 Hz, 4H), 1.12 (s, 9H), 1.11 (s,
9H); 13C{1H} NMR (101 MHz, chloroform-d) δ 151.0, 134.0, 128.1,
114.9, 81.5, 71.5, 66.8, 49.0, 34.9, 27.5, 27.0, 23.0, 20.1; IR 2857,
1101, 932 cm−1; HRMS (ESI) calcd for C21H35INO3Si+ 504.1431,
found 504.1426 (MH+).
69 mg, 77% isolated yield); H NMR (400 MHz, CDCl3) δ 7.25−
7.19 (m, 2H), 7.17−7.09 (m, 3H), 4.20−4.14 (m, 1H), 4.14−4.06
(m, 1H), 4.03−3.98 (m, 2H), 2.79 (ddd, J = 14.1, 9.7, 4.6 Hz, 1H),
2.65 (ddd, J = 13.6, 9.4, 7.3 Hz, 1H), 2.37 (dddd, J = 13.6, 9.3, 7.3, 1.7
Hz, 1H), 1.81−1.66 (m, 1H), 0.97 (s, 9H), 0.94 (s, 9H); 13C{1H}
NMR (101 MHz, CDCl3) δ 141.8, 128.6, 128.3, 125.8, 77.7, 71.1,
39.4, 32.7, 31.0, 27.4, 27.0, 22.8, 19.9; IR 2931, 1174, 1042, 825 cm−1;
HRMS (ESI) calcd for C19H32IO2Si+ 447.1211, found 447.1208
(MH+).
4-(Benzo[b]thiophene-3-yl)-2,2-di-tert-butyl-5-iodo-1,3,2-dioxa-
silinane (48). Synthesized using protocol C; purified using 100%
benzene on Florisil; single diastereomer (colorless oil, 37 mg, 39%);
1H NMR (400 MHz, chloroform-d) δ 8.01 (dd, J = 7.5, 1.3 Hz, 1H),
7.95−7.88 (m, 1H), 7.48−7.26 (m, 3H), 5.61 (d, J = 10.6 Hz, 1H),
4.70 (dt, J = 10.5, 7.9 Hz, 1H), 4.54−4.42 (m, 2H), 1.17 (s, 9H), 1.08
(s, 9H); 13C{1H} NMR (101 MHz, chloroform-d) δ 140.3, 137.9,
137.8, 124.4, 124.3, 123.9, 122.8, 122.5, 75.5, 71.5, 31.3, 27.5, 27.0,
23.0, 20.0; IR 2833, 1428, 1007 cm−1; HRMS calcd for
C19H28IO2SSi+ 475.0624, found 475.0632 (MH+).
2,2-Di-tert-butyl-5-iodo-1,3,2-dioxasilinan-4-yl)pyridine (52).
Synthesized using protocol C; purified using 100% benzene on
Florisil; single diastereomer (colorless oil, 42 mg, 50%); H NMR
(400 MHz, chloroform-d) δ 8.61 (d, J = 2.3 Hz, 1H), 8.51 (dd, J =
4.8, 1.7 Hz, 1H), 7.65 (dt, J = 7.8, 1.9 Hz, 1H), 7.30−7.17 (m, 1H),
5.06 (d, J = 10.4 Hz, 1H), 4.39−4.26 (m, 2H), 4.19 (td, J = 10.3, 5.6
Hz, 1H), 1.02 (s, 9H), 1.02 (s, 9H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 149.7, 149.2, 137.7, 134.5, 123.1, 79.8, 71.4, 33.2,
27.5, 26.9, 23.0, 20.1; IR 2859, 1471, 937 cm−1; HRMS (ESI) calcd
for C16H27INO2Si+ 420.0856, found 420.0845 (MH+).
1
2,2-Di-tert-butyl-5-iodo-1,3,2-dioxasilinan-4-yl)methyl acetate
(49). Synthesized using protocol B; purified using a gradient of 0 to
100% acetone/DCM on Florisil followed by a gradient of 0−100%
acetonitrile in 0.1% TFA-H2O on a RediSep Prep C18 column (100
Å, 5 μm, length 250 mm, i.d.: 20 mm, flow rate of 15 mL/min); single
2,2-Di-tert-butyl-5-iodo-4,4-dimethyl-1,3,2-dioxasilinane (53).
Synthesized using protocol B; purified using a gradient of 0−10%
EtOAc in hexanes on silica gel (light yellow semisolid, 59 mg, 80%
isolated yield); 1H NMR (400 MHz, CDCl3) δ 4.29 (dd, J = 11.8, 3.8
Hz, 1H), 4.24−4.15 (m, 1H), 4.06 (dd, J = 11.1, 3.9 Hz, 1H), 1.50 (s,
3H), 1.43 (s, 3H), 0.94 (s, 9H), 0.93 (s, 9H); 13C{1H} NMR (101
MHz, CDCl3) δ 75.2, 67.7, 37.1, 31.9, 27.3, 26.3, 21.5, 20.3; IR 2967,
1475, 1165, 825 cm−1; HRMS (ESI) calcd for C13H28IO2Si+
371.0898, found 371.0899 (MH+).
1
diastereomer (light yellow oil, 60 mg, 72% yield); H NMR (400
MHz, CDCl3) δ 4.45 (dd, J = 11.8, 2.7 Hz, 1H), 4.27 (dd, J = 11.4,
3.6 Hz, 1H), 4.21 (dd, J = 11.8, 6.0 Hz, 1H), 4.12 (ddd, J = 7.6, 5.6,
3.6 Hz, 1H), 4.07−3.98 (m, 2H), 2.05 (s, 3H), 0.98 (s, 9H), 0.97 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 71.5, 67.9, 66.2,
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residue was purified by chromatography on silica gel to yield 57 as a
colorless oil (41 mg, 83%).
2,2-Di-tert-butyl-4,4-diethyl-5-iodo-1,3,2-dioxasilinane (54).
Synthesized using protocol B; purified using 100% benzene on
Florisil (colorless oil, 47 mg, 59%); 1H NMR (400 MHz, chloroform-
d) δ 4.54 (dd, J = 11.8, 4.5 Hz, 1H), 4.35 (t, J = 11.5 Hz, 1H), 4.16
(dd, J = 11.2, 4.5 Hz, 1H), 2.04 (dt, J = 14.7, 7.3 Hz, 1H), 1.89 (dqd,
J = 14.6, 7.5, 2.4 Hz, 2H), 1.65 (dq, J = 14.8, 7.5 Hz, 1H), 1.05 (s,
9H), 1.03 (s, 9H), 1.06−0.98 (m, 6H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 77.8, 67.3, 35.2, 32.4, 28.4, 27.9, 27.3, 21.6, 21.0, 8.2,
8.2; IR 2860, 1475, 1145 cm−1; HRMS (ESI) calcd for C15H32IO2Si+
399.1216, found 399.1181 (MH+).
Compound 57. Purified using a gradient of 0−10% EtOAc in
hexanes on silica gel (colorless oil, 83%); 1H NMR (400 MHz,
chloroform-d) δ 7.48−7.35 (m, 4H), 7.35−7.26 (m, 1H), 5.22 (dd, J
= 11.3, 2.3 Hz, 1H), 4.33 (ddd, J = 12.5, 11.1, 2.4 Hz, 1H), 4.21 (ddd,
J = 11.0, 4.5, 2.0 Hz, 1H), 2.09 (dddd, J = 14.4, 12.5, 11.3, 4.5 Hz,
1H), 1.89 (dq, J = 14.4, 2.3 Hz, 1H), 1.15 (s, 9H), 1.13 (s, 9H);
13C{1H} NMR (101 MHz, chloroform-d) δ 144.9, 128.3, 127.0,
125.0, 75.9, 64.7, 39.5, 27.5, 27.2, 22.9, 20.1; IR 2859, 1473, 886
cm−1; HRMS (ESI) calcd for C17H29O2Si+ 293.1937, found 293.1938
(MH+).
Compound 44 (70 mg, 0.16 mmol) was dissolved in 0.5 mL of
DMF. To this solution were added sodium azide (0.32 mmol, 2
equiv) and 15-crown-5 (0.32 mmol, 2 equiv) at room temperature.
The temperature of the reaction was gradually increased to 100 °C
(oil bath) and kept at this temperature for 12 h with magnetic stirring.
After consumption of starting material (followed by TLC), the
reaction mixture was diluted with EtOAc and transferred to a
separatory funnel. The organic layer was washed with cold water (3 ×
3 mL). The organic layer was collected, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by chromatography on silica gel to yield compound 58 (24
mg, 43%) as a colorless solid.
2,2-Di-tert-butyl-5-iodo-4-methyl-4-(4,8,12-trimethyltridecyl)-
1,3,2-dioxasilinane (55). Synthesized using protocol B; purified using
benzene on Florisil; mixture of diastereomers (light yellow oil, 81 mg,
70% yield); 1H NMR (400 MHz, CDCl3) δ 4.32−4.19 (m, 2H), 4.06
(dd, J = 8.9, 1.7 Hz, 1H), 1.84 (tdd, J = 13.1, 11.1, 4.6 Hz, 1H), 1.55−
0.97 (m, 23H), 0.94 (d, J = 4.6 Hz, 18H), 0.79 (dd, J = 8.4, 6.6 Hz,
12H); 13C{1H} NMR (101 MHz, CDCl3) δ 76.6, 67.6, 44.2, 44.1,
39.4, 37.52, 37.50, 37.48, 37.45, 37.34, 37.28, 37.23, 37.21, 32.84,
32.82, 32.6, 32.5, 28.0, 27.5, 27.4, 24.83, 24.82, 24.48, 24.42, 23.79,
23.77, 22.75, 22.65, 21.4, 20.4, 20.0, 19.9, 19.83, 19.80, 19.77, 19.70;
IR 2859, 1377, 1464, 1080, 825 cm−1; HRMS (ESI) calcd for
C28H57INaO2Si+ 603.3065, found 603.3049 (MNa+).
Compound 58. Purified using benzene on Florisil; single
1
diastereomer (colorless solid, 54%); H NMR (400 MHz, chloro-
form-d) δ 7.46−7.35 (m, 5H), 5.46 (d, J = 2.0 Hz, 1H), 4.56 (dd, J =
12.5, 1.8 Hz, 1H), 4.39 (dd, J = 12.5, 2.0 Hz, 1H), 3.82 (q, J = 1.9 Hz,
1H), 1.20 (s, 9H), 1.14 (s, 9H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 140.6, 128.2, 127.7, 125.7, 76.3, 66.1, 64.4, 27.7, 27.2,
23.5, 20.7; IR 2860, 1474, 889 cm−1; HRMS (ESI) calcd for
C17H28N3O2Si+ 334.1951, found 334.1960 (MH+).
TBAF in THF (1 M, 0.280 mL, 0.28 mmol) was added to
compound 44 (40 mg, 0.09 mmol) in THF (2 mL) at 0 °C, and the
reaction was warmed to room temperature over 16 h. Following this
time, the reaction mixture was concentrated, and the resulting residue
was purified by chromatography on silica gel to yield 59 (9 mg, 63%)
as a colorless oil.
2,2-Di-tert-butyl-5-iodo-1,3,9-trioxa-2-silaspiro[5.5]undecane
(56). Synthesized using protocol B; purified using 100% benzene on
Florisil (colorless oil, 36 mg, 44%); 1H NMR (400 MHz, chloroform-
d) δ 4.35−4.16 (m, 2H), 4.06 (dd, J = 11.0, 3.4 Hz, 1H), 3.83−3.67
(m, 4H), 2.36−2.17 (m, 2H), 1.67 (dt, J = 13.6, 2.4 Hz, 1H), 1.34
(dt, J = 13.4, 2.3 Hz, 1H), 0.95 (s, 9H), 0.96 (s, 9H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 73.4, 66.6, 63.8, 63.0, 38.5, 37.5, 33.5,
27.5, 27.2, 21.5, 20.3; IR 2861, 1471, 924 cm−1; HRMS (ESI) calcd
for C15H29IO3SiNa+ 435.0828, found 435.0851 (MNa+).
V. Scale-up Procedure. A round-bottom flask was charged with
stir bar, alkene substrate (870 mg, 2.97 mmol, 1 equiv), AgOTf (841
mg, 3.3 mmol, 1.3 equiv), and 25 mL of anhydrous DME. The
reaction vial was immersed in a bath set to −15 °C. I2 (830 mg, 3.2
mmol, 1.2 equiv) was added in one portion. A light-yellow precipitate
formed immediately upon addition of AgOTf. The heterogeneous
mixture was stirred for 2 h at −15 °C and then quenched by addition
of aqueous saturated Na2S2O3. The reaction mixture was diluted with
ethyl acetate and transferred to a separatory funnel. The organic
portion was collected, and the aqueous layer was extracted with two
additional portions of ethyl acetate. The organic fractions were
pooled, dried with MgSO4, and concentrated under reduced pressure.
The resulting residue was purified by chromatography on Florisil
(100% benzene) to yield a light yellow solid (1.14 g, 2.72 mmol, 92%
yield).
Compound 59. Purified using a gradient of 0 to 20% EtOAc in
1
hexanes on silica gel; single diastereomer (colorless oil, 63%); H
NMR (600 MHz, chloroform-d) δ 7.44−7.25 (m, 5H), 4.09 (dd, J =
12.8, 2.4 Hz, 1H), 3.97 (d, J = 2.1 Hz, 1H), 3.84 (dd, J = 12.8, 3.8 Hz,
1H), 3.27 (dt, J = 4.2, 2.4 Hz, 1H), 1.95 (s, 1H); 13C{1H} NMR (101
MHz, chloroform-d) δ 136.6, 128.5, 128.3, 125.7, 62.3, 61.1, 55.5.
HF·pyridine (∼70% HF−30% pyridine, 75 μL) was added to
compound 44 (40 mg, 0.09 mmol) in THF at 0 °C, and the mixture
was stirred for 5 min. The reaction was quenched with saturated
aqueous NaHCO3 and transferred to a separatory funnel. The water
layer was extracted with three portions of ethyl acetate. The organic
layers were collected, pooled, and dried with Na2SO4. After
concentration under reduced pressure, the resulting residue was
VI. Procedures for Derivatization Reactions. 44 (70 mg, 0.16
mmol) was dissolved in 6 mL of DCM. Tributyltin hydride (97 μL,
0.36 mmol) was added, and the reaction was stirred for 12 h at 40 °C
(oil bath). The reaction mixture was concentrated, and the resulting
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purified by chromatography on silica gel to yield 60 (13 mg, 49%) as a
colorless oil.
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Compound 60. Purified using a gradient of 0−40% EtOAc in
hexanes on silica gel (colorless oil, 49%); 1H NMR (400 MHz,
chloroform-d) δ 7.47−7.32 (m, 5H), 5.08 (dd, J = 6.3, 2.5 Hz, 1H),
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(MNa+).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00872.
Expanded procedures, crystal structure data, NMR
spectra and computational details (PDF)
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tions of Alkenyl Phosphoramidates. ChemRxiv 2021, DOI: 10.26434/
chemrxiv.14132177.v1.
Accession Codes
CCDC 2062814 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
■
Corresponding Author
Shyam Sathyamoorthi − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66047, United
States; orcid.org/0000-0003-4705-7349;
Email: ssathyam@ku.edu
Authors
Ranjeet A. Dhokale − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66047, United States
Frederick J. Seidl − Independent Researcher, San Bruno,
California 94066, United States; orcid.org/0000-0001-
9327-4753
Anand H. Shinde − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66047, United
States; orcid.org/0000-0003-1966-8505
Joel T. Mague − Department of Chemistry, Tulane University,
New Orleans, Louisiana 70118, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00872
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by start-up funding provided jointly
by the University of Kansas Office of the Provost and the
Department of Medicinal Chemistry, an NIH COBRE
Chemical Biology of Infectious Diseases Research Project
Grant (P20GM113117), and a New Faculty General Research
Fund Grant.
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