Selective H/D Exchange at Vinyl and Methylidene Groups with D2O Catalyzed by an Iridium Complex

Article abstract of DOI:10.1021/acs.orglett.6b01721

Selective H/D exchange at vinyl and methylidene groups of alkenes with D₂O was promoted by an iridium catalyst generated in situ from a hydroxoiridium complex and N-mesylbenzamide.

Full text of DOI:10.1021/acs.orglett.6b01721

Letter
pubs.acs.org/OrgLett
Selective H/D Exchange at Vinyl and Methylidene Groups with D2O
Catalyzed by an Iridium Complex
Miyuki Hatano, Takahiro Nishimura,* and Hideki Yorimitsu
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: Selective H/D exchange at vinyl and methyl-
idene groups of alkenes with D2O was promoted by an iridium
catalyst generated in situ from a hydroxoiridium complex and
N-mesylbenzamide.
Scheme 1. Ir-Catalyzed Alkylation of N-Sulfonylbenzamides
ntroduction of deuterium into organic molecules by H/D
exchange reaction is a powerful method to directly
I
synthesize deuterium-labeled compounds, which are valuable
for the study of reaction mechanisms and for a variety of
applications in the pharmaceutical and materials industries.1
The development of such H/D exchange methods also enables
the straightforward synthesis of tritiated compounds.2 H/D
exchange processes have been well-studied in organometallic
chemistry, and diverse transition metal catalysts focusing on the
synthesis of deuterated compounds have been developed.1,3
Iridium is one of the most active catalysts for H/D exchange
reactions of aromatic and aliphatic C−H bonds.4 With the
recent development of selective C−H bond functionalization,
there is increasing attention on selective deuteration of alkenyl
moieties.5−9 In 2008, Zhou and Hartwig5 reported Ir-catalyzed
selective H/D exchange at vinyl groups without olefin
isomerization, where the deuterium is transferred from C6D6.
Iridium catalysts containing an aliphatic pincer-type ligand had
high catalytic activity, which permits aromatic C−H bond
deuteration also. Oro and co-workers reported Rh-catalyzed
selective H/D exchange at the β-position of aromatic α-olefins
in the presence of CD3OD or D2O.6 A Ru-catalyzed H/D
exchange reaction of alkenes was reported by Lin, Jia, and co-
workers.7
We recently reported Ir-catalyzed asymmetric alkylation of
aromatic N-sulfonylbenzamides with vinyl ethers (Scheme 1).10
The reaction is efficiently catalyzed by a hydroxoiridium/chiral
diene complex to give the branched adducts in high yields with
high enantioselectivity. Hydridoiridium species II generated by
means of ortho C−H activation of amidoiridium species I is a
key intermediate. The reaction proceeds in the presence of
D2O to afford deuterium incorporation into the adduct, the
substrate amide, and the vinyl ether. In this deuteration,
hydridoiridium II should undergo H/D exchange, and the
following deuterium transfer to the vinyl ether should occur
through reversible insertion and β-hydrogen elimination. While
this deuterium-labeling experiment was thus helpful to
understand the reaction mechanism, interestingly, similar
deuterium incorporation was also observed for alkenes that
are unreactive toward the amide. The results prompted us to
apply species II as a catalyst for the H/D exchange reaction of
alkenes using D2O. Here we report that selective H/D
exchange of vinyl and methylidene groups is promoted by an
iridium catalyst generated in situ from a hydroxoiridium
complex and N-mesylbenzamide.
Our initial studies (Table 1) focused on the H/D exchange
of p-methoxystyrene (2a) in the presence of an iridium
complex because styrene derivatives did not undergo the
alkylation of N-sulfonylbenzamides in our previous studies.10
Treatment of 2a with 20 equiv of D2O in the presence of a
catalytic amount of [Ir(OH)(cod)]2 (5 mol % Ir, cod = 1,5-
cyclooctadiene) and amide 1a (10 mol %), which is a good
Received: June 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01721
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Ir-Catalyzed H/D Exchange of 2a with D2O
b
c
c
c
entry
1
x, y
yield (%)
D1
D2
D3
a
Scheme 2. Ir-Catalyzed H/D Exchange of Vinyl Groups
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
−
1b
1b
1b
1b
1b
5, 10
5, 10
5, 10
5, 10
5, 0
98
99
96
92
94
97
99
92
91
0
92
91
0
90
91
0
0
0
0
0
0
0
0, 5
0
0
0
5, 5
92
92
90
92
91
91
90
91
91
91
90
91
d
1, 1
88
d
0.1, 0.1
0.1, 0.1
94
d
e
10
96
a
Reaction conditions: 2a (0.10 mmol), amide 1, [Ir(OH)(cod)]2, and
D2O (20 equiv) in THF (0.40 mL) at 70 °C for 3 h. For entry 8, 0.50
mmol of 2a was used. For entries 9 and 10, 5.00 mmol of 2a was used.
b
See the Supporting Information for details. Determined by 1H NMR
analysis using nitromethane as an internal standard. For entries 3−6,
c
the percentages of recovered 2a are shown. Deuterium contents (%)
d
e
1
were determined by H NMR analysis. Isolated yield. For 20 h.
substrate in the Ir-catalyzed ortho-alkylation with vinyl ethers,10
in THF at 70 °C for 3 h gave deuterated [D]-2a (Table 1, entry
1). The deuterium was selectively introduced into the vinyl
group of 2a (D1−D3, 90−92%), and no deuterium was detected
on the aromatic ring or the methoxy group. The high catalytic
activity was also observed when a catalytic amount of N-
mesylbenzamide (1b) was used (entry 2), whereas the use of
either N-mesylpivalamide (1c) (entry 3) or benzamide (1d)
(entry 4) did not promote the H/D exchange. The combined
use of [Ir(OH)(cod)]2 and amide 1b was essential for the
present reaction (entries 5 and 6). An equimolar amount of
amide 1b with respect to iridium was enough to promote the
reaction (entry 7). The H/D exchange was achieved by use of a
reduced amount of the catalyst (entries 8−10): a high level of
deuterium incorporation was observed in the reaction with only
0.1 mol % Ir catalyst for a prolonged reaction time (20 h)
(entry 10). The observed deuterium contents are close to the
maximum theoretical level of deuteration attainable under the
reaction conditions (92.9% for 1 mol % Ir catalyst).11 The
reactions in other solvents, such as toluene, 1,4-dioxane,
acetonitrile, and ethyl acetate, also displayed the same level of
deuterium incorporation as observed in THF under a 5 mol %
loading of the Ir catalyst.11
Higher deuterium content (98%) was achieved by the use of
a quite large excess of D2O (200 equiv) (eq 1). Alternatively,
treatment of 2a twice with D2O (20 equiv each) by replacing
the first D2O phase with fresh D2O led to the exchange of
vinylic protons with 98% deuterium incorporation (eq 2).
Scheme 2 summarizes the results obtained for the H/D
exchange of vinyl groups with D2O (20 equiv). Vinyl arenes
2b−k are good substrates, giving the deuterated alkenes [D]-
2b−k in high yields with high deuterium contents; the H/D
exchange selectively occurred at the vinyl group, and only a
trace amount of deuterium at the ortho positions of the phenyl
a
Reaction conditions: 1b (1 mol %), [Ir(OH)(cod)]2 (0.0025 mmol,
1 mol % Ir), 2a (0.50 mmol), and D2O (10 mmol, 20 equiv) in THF
(0.40 mL) at 70 °C for 3 h. Isolated yields are shown. Deuterium
b
1
contents were determined by H NMR analysis. Performed with 2
c
mol % Ir. Deuterium contents were determined by 1H NMR analysis
of 1,2,4,5-tetrafluoro-3-methoxy-6-(vinyl-d3)benzene derived from
[D]-2k. Performed with 5 mol % Ir.
d
group was observed for 2b−f. Chloro (2d) and bromo groups
(2e−g) were tolerated in the reaction. In the reaction of 3-
vinylindole 2j, a significant amount of deuterium at the 2-
position (15%) was observed. The present catalytic system was
successfully applied to the H/D exchange of pentafluorostyrene
(2k) and N-vinylpyrrolidone (2l), which are useful monomers
for important synthetic materials, fluorinated polymers12 and
poly(N-vinylpyrrolidone),13 respectively. The H/D exchange of
vinyl silane 2m took place efficiently. Unfortunately, the
present catalytic system cannot be applied to the H/D
exchange of terminal alkenes having allylic protons such as 1-
octene because of fast isomerizations into inactive internal
alkenes.
It should be noted that the hydroxoiridium/amide 1b catalyst
displayed high catalytic activity toward the H/D exchange of
methylidene groups without isomerization of the alkenes
B
DOI: 10.1021/acs.orglett.6b01721
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Scheme 3). The reaction of α-methylstyrene (3a) with D2O
gave [D]-3a, whose methylidene group was selectively
The pioneering studies on α-elimination in alkyliridium
complexes by Crabtree and co-workers provide us mechanistic
insight into the present H/D exchange reaction.16,17 They
reported that a stoichiometric reaction of the iridium dihydride
IrD2(OCOCF3)(P(4-FC6H4)3)2 with α-methylstyrene gave a
monodeuterated product, which was proposed to be formed by
way of α-elimination followed by β-elimination.16a An
alternative reaction pathway involving alkane C−H activation
has been proposed in subsequent studies.16b We observed the
formation of the hydridoiridium species A (intermediate II in
Scheme 1) by 1H NMR spectroscopy in the reaction of
[Ir(OH)(cod)]2 with 1b in CD3CN (Scheme 4a).11 In our
Scheme 3. Ir-Catalyzed H/D Exchange of Methylidene
a
Groups
Scheme 4. Plausible Reaction Pathways
a
The reactions of alkenes 3 were performed in the presence of
[Ir(OH)(cod)]2 (2 mol % Ir), amide 1b (2 mol %), and D2O (20
equiv) in THF at 70 °C for 3 h. Isolated yields are shown. Deuterium
b
c
contents were determined by 1H NMR analysis. For 20 h. Performed
d
with 5 mol % Ir. Performed with 5 mol % Ir for 14 h.
deuterated, with only a small amount of deuterium
incorporation observed at the methyl group (1% D). Besides
simple alkenes 3b and 3c,14 allylic ether 3d, allylic imide 3e, and
isopropenyl ether 3f were deuterated at the methylidene groups
with high regioselectivity. To the best of our knowledge, there
have been no reports on the catalytic selective H/D exchange
reaction of methylidene groups of alkenes having aromatic
rings.15
The H/D exchange reaction of trans-stilbene (4) did not take
place at all (eq 3), whereas cis-stilbene (5) was transformed into
catalytic system, an insertion/β-elimination route (Scheme 4b)
via aryldeuterioiridium Ir-D is most likely to permit the H/D
exchange of vinyl groups in Table 1 and Scheme 2. In the H/D
exchange of methylidene groups shown in Scheme 3, primary
alkyliridium B formed by the insertion possibly undergoes α-
elimination to form carbene complex C, and a subsequent 1,2-
deuteride shift18 gives the deuterated compound (Scheme
4c).19 The α-elimination route is consistent with the fact that
the isomerization of the alkene moiety caused by species D was
monodeuterated trans-stilbene ([D]-4) in the presence of D2O
(eq 4). Complete conversion of 5 was achieved in the presence
of 5 mol % Ir catalyst after 20 h to give [D]-4 in 96% yield,
which contained 90% deuterium (eq 5). The observed
isomerization of 5 accompanied by the monodeuteration can
be explained by an insertion/β-elimination mechanism; a bond
rotation in alkyliridium species III occurs to form conformer
IV, which leads to the formation of trans-stilbene. However, the
rotation from IV to III leading to cis-stilbene is disfavored
because of its steric effect. The present selectivity is different
from that observed in the Ru catalysis by Lin, Jia, and co-
workers, who reported that deuterated trans-stilbene was
formed from both trans-stilbene and cis-stilbene.7
not observed for the methylidene compounds.20
In summary, we have developed an Ir-catalyzed selective H/
D exchange of vinyl and methylidene groups that is promoted
by an iridium catalyst generated in situ from a hydroxoiridium
complex and N-mesylbenzamide. Experimental studies are
underway to gain detailed mechanistic insights into the present
catalytic system.
C
DOI: 10.1021/acs.orglett.6b01721
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01721.
■
S
Experimental procedures and NMR spectra (PDF)
(5) Zhou, J.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 5783.
AUTHOR INFORMATION
Corresponding Author
(6) (a) Di Giuseppe, A.; Castarlenas, R.; Perez-Torrente, J. J.; Lahoz,
́
■
F. J.; Polo, V.; Oro, L. A. Angew. Chem., Int. Ed. 2011, 50, 3938. (b) Di
́
Giuseppe, A.; Castarlenas, R.; Perez-Torrente, J. J.; Lahoz, F. J.; Oro,
L. A. Chem. - Eur. J. 2014, 20, 8391.
*tnishi@kuchem.kyoto-u.ac.jp
(7) Tse, S. K. S.; Xue, P.; Lin, Z.; Jia, G. Adv. Synth. Catal. 2010, 352,
1512.
Notes
The authors declare no competing financial interest.
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Smart, C. J. Organometallics 1989, 8, 602. (c) Kohl, G.; Rudolph, R.;
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G.; Grotjahn, D. G. J. Am. Chem. Soc. 2009, 131, 10354.
(e) Rybtchinski, B.; Cohen, R.; Ben-David, Y.; Martin, J. M. L.;
Milstein, D. J. Am. Chem. Soc. 2003, 125, 11041.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant
JP15H03810.
■
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DOI: 10.1021/acs.orglett.6b01721
Org. Lett. XXXX, XXX, XXX−XXX