Metal-Free Transfer Hydroiodination of C-C Multiple Bonds

Article abstract of DOI:10.1021/jacs.8b12318

The design and a gram-scale synthesis of a bench-stable cyclohexa-1,4-diene-based surrogate of gaseous hydrogen iodide are described. By initiation with a moderately strong Br?nsted acid, hydrogen iodide is transferred from the surrogate onto C-C multiple bonds such as alkynes and allenes without the involvement of free hydrogen iodide. The surrogate fragments into toluene and ethylene, easy-to-remove volatile waste. This hydroiodination reaction avoids precarious handling of hydrogen iodide or hydroiodic acid. By this, a broad range of previously unknown or difficult-to-prepare vinyl iodides can be accessed in stereocontrolled fashion.

Full text of DOI:10.1021/jacs.8b12318

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Article
Metal-Free Transfer Hydroiodination of C-C Multiple Bonds
Weiqiang Chen, Johannes Walker, and Martin Oestreich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12318 • Publication Date (Web): 14 Dec 2018
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Metal-Free Transfer Hydroiodination of C‒C Multiple Bonds
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Weiqiang Chen, Johannes C. L. Walker, and Martin Oestreich*
Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 115, 10623 Berlin, Germany
Supporting Information Placeholder
ABSTRACT: The design and a gram-scale synthesis of a bench-stable cyclohexa-1,4-diene-based surrogate of gaseous hydrogen iodide
are described. By initiation with a moderately strong Brønsted acid, hydrogen iodide is transferred from the surrogate onto C‒C multiple
bonds such as alkynes and allenes without the involvement of free hydrogen iodide. The surrogate fragments into toluene and ethylene,
easy-to-remove volatile waste. This hydroiodination reaction avoids precarious handling of hydrogen iodide or hydroiodic acid. By this, a
broad range of previously unknown or difficult-to-prepare vinyl iodides can be accessed in stereocontrolled fashion.
the Brønsted-Acid-Initiated Transfer Hydrohalogenation
INTRODUCTION
of Alkynes (bottom) (A‒ = Counteranion)
Hydrogen iodide (HI) is a toxic and corrosive gas that is com-
monly handled in the form of an equally corrosive, concentrated
aqueous solution called hydroiodic acid. It can be used directly,
and the Cativa™ process is an example of an industrial applica-
tion,1 but in-situ generation of hydrogen iodide is often more
practical on the laboratory scale. Representative procedures make
use of alkali metal iodides,2 also together with Me3SiCl,3 or
Me3SiI directly,4 as well as elemental iodine5‒10 as the iodine
source; activation of Me3SiI, I2, and PI3 on alumina was especially
investigated.5,6 Recently, Lautens and co-workers introduced
Et3N·HI and primary alkyl iodides as safe surrogates of HI.11
Their elegant approach is based on oxidative addition of HI to
palladium(0) or palladium(0)-catalyzed dehydrohalogenation of
the alkyl iodide. Both methods arrive at the same H‒Pd(II)‒X
intermediate that subsequently participates in the hydroiodination
of 1,6-enynes. The overall process is a transition-metal-catalyzed
transfer hydroiodination.12,13
We have been engaged in the development of metal-free trans-
fer processes driven by aromatization of cyclohexa-1,4-dienes.14
For example, cyclohexa-1,4-dienes I and II are surrogates of
hydrosilanes and dihydrogen, respectively (Scheme 1, top). The
strong boron Lewis acid B(C6F5)3 then promotes alkene transfer
hydrosilylation14 with I as well as transfer hydrogenation16 with
II;17 catalysis by several Brønsted acids was also demonstrated for
II.18 An extension of this strategy to hydrohalic acid (HX) surro-
We report here the gram-scale synthesis of an HI surrogate
similar to the generic structure IV and its application to the
gates III is not realistic due to their innate chemical instability
Brønsted-acid-initiated transfer hydroiodination of alkynes,19
(Scheme 1, top). To prevent rapid aromatization, we designed
alkenes20 and allenes21 (V→VII for X = I, Scheme 1, bottom
right).
stable systems IV with an additional ethylene unit where we
deemed controlled release of HX feasible (Scheme 1, bottom left).
We hoped that this measure would simply translate into the for-
mation of ethylene gas. However, we had to learn that derivatives
RESULTS AND DISCUSSION
of IV are either inert toward or do not react with B(C6F5)3 in the
planned way. Hence, we turned toward Brønsted-acid catalysis,18
cognizant that the nucleofuge/electrofuge situation in IV could
now be reverse to that in I and II. Halide abstraction from IV by
an assumed carbocation intermediate VI by way of an iodonium
ion intermediate is probably favored over hydride abstraction18
from IV (Scheme 1, bottom right).
Surrogate Identification and Preparation. Our investigation
began with the identification and preparation of a robust surrogate
(Figure 1). Parent compound 122 seemed an obvious choice but
was not sufficiently stable. Aromatization was again the problem.
A quaternary carbon atom in the ring would forestall aromatiza-
tion, and easy-to-access derivative 222 was indeed stable. Howev-
er, its high molecular weight and potential difficulties associated
with removing the non-volatile biphenyl waste made it less attrac-
tive. We eventually arrived at low-molecular-weight structure 3
Scheme 1. Cyclohexa-1,4-diene-Based Surrogates (top) and
Modified HX Surrogate and Assumed Catalytic Cycle of
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that would release toluene and ethylene as waste. Its synthesis was
come, and α-iodostyrene was obtained chemoselectively in high
yield (entry 10).
accomplished in seven routine synthetic operations with five
purifications (Scheme 2). The ethylene unit was established by
Wittig homologation (6→7) after Birch alkylation and adjustment
of the oxidation level (4→5→6). The primary alkyl iodide was
installed by an Appel reaction of the corresponding alcohol (8→3).
The sequence was scalable, and the four-step chain extension
5→8 was also possible on gram scale without purification of the
intermediates (gray arrow, Scheme 2).
Table 1. Optimization of the Brønsted-Acid-Initiated
Transfer Hydroiodination of Alkynesa
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T (°C)
for t (h)
yield of
yield of
entry acid
solvent
C6D6
10 (%)b
11 (%)b
Figure 1. Potential cyclohexa-1,4-diene-based surrogates (see the
Supporting Information for details).
1
Tf2NH
100
75
12
for 12
100
Scheme 2. Synthesis of HI Surrogate 3
2c
3c
4
TfOH
C6D6
< 1
trace
87
< 1
trace
13
for 6
100
[H(OEt2)2]+ C6D6
[BArF ]–
for 12
100
4
TsOH
TsOH·H2O
none
C6D6
for 8
100
5
C6D6
47d
< 1
59
10
for 12
100
6
C6D6
< 1
24
for 6
100
7
TsOH
TsOH
TsOH
TsOH
TsOH
C6D5Cl
for 12
8
1,2-C6D4Cl2 100
for 24
80
63
32
Reaction conditions: a) Na (4.0 equiv), tBuOH (1.0 equiv), NH3, ‒78
°C, 1 h; MeI (4.0 equiv), THF, ‒78 °C to RT, overnight; b) LiAlH4 (2.0
equiv), THF, 0 °C; c) (COCl)2 (1.5 equiv), DMSO (2.0 equiv), CH2Cl2,
‒78 °C, 30 min; Et3N (excess), ‒78 °C to RT, 30 min; d)
[Ph3PCH2OMe]+Cl‒ (1.2 equiv), nBuLi (2.5 M in hexanes, 1.1 equiv), 0
°C to RT, overnight; HCl in H2O (32%), 0 °C, 2 h; e) NaBH4 (2.0 equiv),
THF, 0 °C to RT, overnight; f) Ph3P (1.3 equiv), I2 (1.3 equiv), imidazole
(1.3 equiv), CH2Cl2, 0 °C to RT, overnight.
9
C6D12
50
< 1
< 1
48
for 8
80
e
10
11f
C6D6/C6D12
C6D6
80
for 8
100
trace
for 18
aUnless otherwise noted, reactions on a 0.030 mmol scale in 0.5 mL of the
indicated solvent. Determined by H NMR spectroscopy by the addition
Optimization and Byproduct Assignment. With gram quanti-
ties of HI surrogate 3 in hand, we tested various Brønsted acids in
the transfer hydroiodination of phenylacetylene (9→10, Table 1).
The outcome of this initial screening in benzene was mixed with
regard to the pKa values (entries 1‒4). TfOH and
b
1
c
of 1,4-dioxane as internal standard after the indicated time. Decomposi-
tion of 9. dStyrene detected in significant amounts (14% yield). e2:1 ratio.
fAddition of 9 after full consumption of 3.
[H(OEt2)2]+[BArF ]−23 promoted the decomposition of 9 but
4
Tf2NH and TsOH facilitated the desired HI transfer from 3 to 9.
The fragmentation pieces of 3, that is toluene and ethylene, were
detected in the 1H NMR spectrum (see the Supporting Information
for details). Using the relatively weak acid TsOH is already highly
attractive, and the use of its monohydrate would have been even
more so. TsOH·H2O did initiate the reaction but the presence of
water was detrimental (entry 5). No reaction was seen in the
absence of added acid (entry 6). Substantial amounts of an unex-
pected compound, characterized as 11, were found in all of the
successful examples. Its proportion increased in more polar arene
solvents such as chloro- and 1,2-dichlorobenzene (entries 7 and 8).
Conversely, the formation of 11 was fully suppressed in cyclo-
hexane but the yield was diminished (entry 9). By using benzene
together with cyclohexane as co-solvent, that problem was over-
Exclusive formation of 11 was achieved when substrate 9 was
added to the reaction after full consumption of surrogate 3 (entry
11). This experiment supports the notion that no free HI is in-
volved in the transfer process. New compound 11 apparently
originates from the HI surrogate 3. We assume that it is formed by
alkene protonation followed by Wagner‒Meerwein rearrangement
of either alkyl group; evidence for subsequent aromatization came
1
from the detection of trace amounts of H2 in the H NMR spec-
trum (see the Supporting Information for details). An alternative
way of the formation of 11 could be by hydride abstraction, that is
one of the endocyclic methylene hydrogen atoms becoming the
nucleofuge (see Scheme 1). Treatment of 3 with the trityl cation
as hydride acceptor rapidly furnished 11, here through the inter-
mediacy of Wheland complex 12 that again undergoes a 1,2-alkyl
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shift24 (Scheme 3). Finally, under the palladium(0)-catalyzed
Similar results were seen with internal alkyl/aryl-substituted
triple bonds, and even a propargyl chloride was converted into the
corresponding allylic system 10k in moderate yield. A tethered
triple bond as in 10m remained untouched. Also, ar-
yl/aryl-substituted 10l formed in moderate yield. However, the
reaction of purely alkyl-substituted substrates was not clean; e.g.,
oct-4-yne yielded the desired vinyl iodide in 28% NMR yield but
could not be further purified (not shown). This is presumably due
to the presence of an aliphatic rather than aromatic group at R1 of
vinyl cation VI (cf. Scheme 1), leading to both poorer stabiliza-
tion of the cation and the availability of alternative reaction path-
ways.
conditions reported by Lautens and co-workers for the dehydro-
halogenation of alkyl iodides,11a no productive reactivity occurred
with only isomerization of HI surrogate 3 to the corresponding
cyclohexa-1,3-diene observed (not shown).
Scheme 3. Rearrangement of the HI Surrogate Initiated by
Hydride Abstraction
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Substrate Scope. The scope of the TsOH-initiated transfer hy-
droiodination of C–C triple bonds was then examined. It quickly
became clear though that purification of the obtained products is
challenging. Its success was dependent on the procedure em-
ployed for the individual substrate as different procedures caused
slightly different compositions of byproducts. We therefore con-
tinued with C6H6 at 100 °C (Method A as in Table 1, entry 4) and
C6H6/C6H12 at 80 °C (Method B as in Table 1, entry 10) to sim-
plify product isolation. Nine terminal (Table 2) and four internal
alkynes (Figure 2) were brought to reaction with HI surrogate 3.
Yields were generally good for the synthesis of α-iodostyrenes
and the functional-group tolerance acceptable. It is noteworthy
that the reaction even works with electron-withdrawing substitu-
ents present at the aryl group as in 10f‒h (entries 6‒8). A delicate
CHO group as in 10g was compatible (entry 7), as was a CN
group as in 10h, albeit in lower yield (entry 8). The borylated
derivative 10i was obtained in decent yield in view of the fact the
reaction mixture is heated at 80 °C for 24 h (entry 9). Routes to
formylated α-iodostyrenes are rare25 and to the best of our
knowledge this is the first reported preparation of a borylated
α-iodostyrene.26 This methodology therefore offers valuable
access to these versatile building blocks.
Figure 2. Examples of the Brønsted-acid-initiated transfer hydroio-
a
dination of internal alkynes. Reaction conditions: Method A: TsOH (10
mol %), C6H6, 100 °C.
The transfer hydroiodination of cycloalkenes to give secondary
alkyl iodides was possible when using the stronger Brønsted-acid
Tf2NH but the results were rather poor. Iodocyclopentane (20%),
iodocyclohexane (40%), and iodocycloheptane (38%) were all
formed in low to moderate yield (see the Supporting Information
for details). The rearrangement of the HI surrogate (3→11; cf.
Table 1, entry 11 and Scheme 3) outrivaled the transfer process in
these reactions. We explain this by similar reactivity of the double
bonds in the substrate and the surrogate.
Interestingly, α,β-unsaturated acceptors were particularly suc-
cessful participants in the transfer hydroiodination (Scheme 4).
Despite their intrinsically electron-poor nature, the use of the
stronger acid Tf2NH overcame their lack of reactivity, and 14a
was predominantly isolated as its E isomer. Methods for the E
selective preparation of β-iodo acrylates are rare.27 Use of condi-
tions previously reported by Piers and co-workers (NaI/AcOH)28
produced the Z isomer in 85% yield (see the Supporting Infor-
mation for details), highlighting the novel reactivity of HI surro-
gate 3. A variety of carbonyl functionalities were tolerated to
produce carboxylic acid, amide, and ketone derivatives 14b–d in
good to excellent yields predominantly with Z configuration.
Routes to β-iodo acrylamides are scarce,29 and variation of the
β-alkyne substitution revealed this to be a general route to this
class of compounds. In all cases, the two geometrical isomers
were either separable by flash column chromatography on silica
gel or the Z isomer was formed exclusively. As before, elec-
tron-withdrawing substitutents such as those in 14e–h were toler-
ated but in this case electron-donating substituents as in 14i–j also
demonstrated excellent reactivity. Heteroaromatic substituents as
in 14l and 14m were also amenable to the reaction and, im-
portantly, aryl substitution was not a requirement for reactivity,
allowing for the formation of acrylamides bearing aliphatic sub-
stituents as in 14n and 14o. We were also able to prepare diene
14p from the corresponding enyne 13p (gray box). In this case, no
reaction at the alkene site was observed.
Table 2. Scope of the Brønsted-Acid-Initiated Transfer
Hydroiodination of Terminal Alkynesa
entry 9 with X
method
time (h)
yield of 10 (%)b
1
9a (X = H)
A
B
B
B
A
A
B
A
B
8
81 (10a)
65 (10b)
61 (10c)
46 (10d)
86 (10e)
70 (10f)
59 (10g)
23 (10h)
44 (10i)
2c
3c
4
9b (X = 4-Me)
9c (X = 3-Me)
9d (X = 2-Me)
9e (X = 4-Cl)
9f (X = 4-F)
24
12
24
8
5
6
8
7
9g (X = 4-CHO)
9h (X = 4-CN)
9i (X = 4-Bpin)
24
24
24
8
Scheme 4. Scope of the Brønsted-Acid-Initiated Transfer
Hydroiodination of Activated Alkynesa
9
aReaction conditions: Method A: TsOH (10 mol %), C6H6, 100 °C;
Method B: TsOH (10 mol %), C6H6/C6H12 2:1, 80 °C. bIsolated yield after
flash chromatography on silica gel.
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mixtures as seen in the ca. 2:1 formation of 16j and 16j’ (gray
box). Allenes lacking the electron-withdrawing carbonyl func-
tionality such as those bearing only aromatic substitution were not
suitable substrates and decomposed under the reaction conditions.
Scheme 5. Scope of the Brønsted-Acid-Initiated Transfer
Hydroiodination of Activated Allenesa
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aObtained from 15d (R1 = OiPr). bTf2NH (10 mol %), 140 °C, 5 d.
cTf2NH (10 mol %), 100 °C, 24 h.
aThe geometrical isomers were separable by flash column chromatog-
raphy and were isolated individually.
CONCLUSION
To summarize, we introduced here a new transfer process that
avoids handling of gaseous hydrogen iodide or its aqueous solu-
tion. Free HI is not even formed in this proton-initiated transfer
hydroiodination of alkynes as well as allenes. Iodide abstraction,
probably by way of an iodonium ion intermediate, from the eth-
ylene tether of the cyclohexa-1,4-diene-based surrogate leads to
its almost traceless fragmentation into toluene and ethylene ac-
companied by release of a proton. The method provides access to
a wide range of hydroiodinated species, many of which have
either not be accessed previously or were difficult to prepare.
Further investigations into the mechanistic details of the reaction
and the extension of this strategy to other HX transfer reactions
are currently underway in our laboratory.35
Interestingly, individual resubjection of the isolated Z and E
isomers of amide 14i to the acidic conditions led to no observable
isomerization. This suggests that the reaction operates under
kinetic rather than thermodynamic control, and that prolonged
heating would not result in changes to the isomer ratio. The rea-
son for the varying quantities of E and Z isomers is, however,
unclear at this stage.
HI surrogate 3 also proved proficient at the transfer hydroio-
dination of allene derivatives (Scheme 5). Previous work by Ma
and co-workers had demonstrated the use of HI generated in situ
from NaI and AcOH to form primarily β-iodo-β,γ-unsaturated
esters from allenes.21f Under our reaction conditions, we instead
formed β-iodo-α,β-unsaturated ester 16a exclusively in 61% yield
from allene 15a, and with excellent control of the double bond
ASSOCIATED CONTENT
Supporting Information
geometry.30
Alternative
routes
to
tetrasubstituted
β-iodo-α,β-unsaturated carbonyl species either give the Z isomer
as the major product31 or rely on specially designed substrates to
deliver the E isomer.32,33 Exploring the scope of the reaction, a
number of carbonyl derivatives were tolerated to provide a small
collection of tetrasubstituted E-alkenes 16b‒f. Interestingly, the
isopropyl ester moiety was cleaved in situ to give carboxylic acid
16c in 83% yield. No hydrolysis was seen for ethyl or methyl
ester derivatives 16a or 16b, suggesting that the transformation
occurred via cleavage of the alkyl C–O bond and formation of the
secondary isopropyl cation.34 Ester 16g, which lacks substitution
at the α-position, was formed in high yield and as almost exclu-
sively the E isomer. Starting from the corresponding alkyne using
the method outlined in Scheme 4 led to the same product but in
lower yield and poorer stereoselectivity. Extended aliphatic or
aromatic substitution at the α-position as in 16h and 16i was also
tolerated, although the latter only in low yield. Adding substitu-
tion at the γ-position of the allene led to the formation of product
Experimental procedures and spectral data for all new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
martin.oestreich@tu-berlin.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the China Scholarship Council
(predoctoral fellowship to W.C., 2016−2020), the Alexander von
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(14) For a review, see: Keess, S.; Oestreich, M. Cyclohexa-1,4-dienes in
Humboldt Foundation (Theodor Heuss Fellowship to J.C.L.W.,
2017–2018), and the Deutsche Forschungsgemeinschaft (Oe
249/18-1). M.O. is indebted to the Einstein Foundation Berlin for
an endowed professorship. We thank Dr. Alice Lefranc for her
initial attempts to prepare HI surrogates based on benzene and
Emin Topal for his experimental contributions (both TU Berlin).
transition-metal-free ionic transfer processes. Chem. Sci. 2017, 8,
4688–4695.
(15) For a review of transfer hydrosilylation, see: (a) Oestreich, M.
Transfer Hydrosilylation. Angew. Chem., Int. Ed. 2016, 55, 494–499.
(b) Simonneau, A.; Oestreich, M. 3-Silylated Cyclohexa-1,4-dienes
as Precursors for Gaseous Hydrosilanes: The B(C6F5)3-Catalyzed
Transfer Hydrosilylation of Alkenes. Angew. Chem., Int. Ed. 2013,
52, 11905–11907. (c) Simonneau, A.; Oestreich, M. Formal SiH4
chemistry using stable and easy-to-handle surrogates. Nat. Chem.
2015, 7, 816–822.
(16) Chatterjee, I.; Qu, Z.-W.; Grimme, S.; Oestreich, M.
B(C6F5)3-Catalyzed Transfer of Dihydrogen from One Unsaturated
Hydrocarbon to Another. Angew. Chem., Int. Ed. 2015, 54, 12158–
12162.
(17) For related transfer processes using cyclohexa-1,3-diene-based
surrogates, see: Yuan, W.; Orecchia, P.; Oestreich, M.
Cyclohexa-1,3-diene-based dihydrogen and hydrosilane surrogates
in B(C6F5)3-catalysed transfer processes. Chem. Commun. 2017, 53,
10390–10393.
(18) Chatterjee, I.; Oestreich, M. Brønsted Acid-Catalyzed Transfer
Hydrogenation of Imines and Alkenes Using Cyclohexa-1,4-dienes
as Dihydrogen Surrogates. Org. Lett. 2016, 18, 2463–2466.
(19) (a) See References [2,5b,6,7,8]. (b) Campos, P. J.; García, B.;
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(22) The syntheses of surrogates 1 and 2 are described in the Supporting
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(30) Similar (E)-β-iodo-α,β-unsaturated esters have previously been
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quantities and together with the corresponding β,γ-unsaturated ester
and dihalogenated products. See Reference 20g.
(31) (a) See Reference 25c. (b) Chen, J.-M.; Huang, X.
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(35) HBr and HCl surrogates with the same platform as HI surrogate 3
are chemically more robust and will require further modification.
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