Iridium-Catalyzed Highly Efficient and Site-Selective Deoxygenation of Alcohols

Article abstract of DOI:10.1021/acscatal.8b02495

An iridium-catalyzed, highly efficient, and site-selective deoxygenation of primary, secondary, and tertiary alcohols has been realized, under the assistance of a 4-(N-substituted amino)aryl directing group. Only the hydroxyl adjacent to the directing group can be deoxygenated. The deoxygenation is performed in water, with formic acid as both the promoter and hydride donor. Excellent yields and functionality tolerance, as well as high efficiency (S/C up to 1000 000, TOF up to 445 000 h^-1), are obtained. The kinetic isotope effect studies show that hydride formation is the rate-determining step, and the deoxygenation follows an S_N1-type pathway. The deoxygenation protocol has been demonstrated useful in the structural modification of naturally occurring ketones and steroids.

Full text of DOI:10.1021/acscatal.8b02495

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Article
Iridium-catalyzed highly efficient and site-selective deoxygenation of alcohols
Shiyi Yang, Weiping Tang, Zhanhui Yang, and Jiaxi Xu
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ACS Catalysis
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Iridium-catalyzed highly efficient and site-selective deoxygen-
ation of alcohols
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Shiyi Yang, † Weiping Tang, ‡,§ Zhanhui Yang*,† and Jiaxi Xu*,†
† State Key Laboratory of Chemical Resource Engineering, College of Science, Beijing University of Chemical Tech-
nology, Beijing 100029, P. R. China
‡ School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA
§ Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
ABSTRACT: An iridium-catalyzed highly efficient and site-selective deoxygenation of primary, secondary, and tertiary al-
cohols has been realized, under the assistance of an 4-(N-substituted amino)aryl directing group. Only the hydroxyl adja-
cent to the directing group can be deoxygenated. The deoxygenation is performed in water, with formic acid as both pro-
moter and hydride donor. Excellent yields and functionality tolerance, as well as high efficiency (S/C up to 1,000,000, TOF
up to 445,000 h-1), are obtained. The kinetic isotope effect studies show that hydride formation is the rate-determining step,
and the deoxygenation follows an SN1-type pathway. The deoxygenation protocol has been demonstrated useful in the struc-
tural modification of naturally occurring ketones and steroids.
KEYWORDS: iridium catalysis • deoxygenation • directing group • site-selectivity • high efficiency • water solvent
1. Introduction
Deoxygenation of alcohols to the corresponding alkanes
has been credited with high importance and wide applica-
tions, especially in the construction and late-stage modifi-
cation of high-value chemicals, bioactive compounds, and
natural products.1 The Barton-McCombie deoxygenation
and its various modifications are classical methods to
mainly deoxygenate the sterically encumbered secondary
alcohols (Scheme 1a, i).1b,e,2 Deoxygenation of primary alco-
hols always requires conversions of the hydroxyls to good
leaving groups (Scheme 1a, ii).3a-h The Ireland protocol
(phosphoryl installation followed by lithium-ammine re-
duction) is versatile to deoxygenate primary, secondary,
and tertiary alcohols.3i In light of the low step-efficiency of
the above protocols, direct deoxygenation of free alcohols
is highly preferred. Reported methods include transition-
metal-catalyzed hydrogenation (Scheme 1b, iii),4 and acid-
catalyzed or -mediated reduction with hydride species
(Scheme 1b, iv).5 However, the site-selectivity of deoxygen-
ation varies from conditions and reagents. Recently, pri-
mary alcohol deoxygenations were selectively realized
based on oxidative dehydrogenation and subsequent
6a
Wolff-Kishner reduction under the iridium, ruthenium,
6b and manganese 6c catalysis (Scheme 1b, v). Despite of the
above advances, challenges still exist, especially in the sin-
Scheme 1. Previous and our deoxygenation protocols.
gle-step deoxygenation. The scope of hydroxyl (primary,
Based on our previous success on the highly efficient
secondary, or tertiary) and site-selectivity constitute the
transfer hydrogenation of a broad range of aldehydes and
main issues that are still not fully addressed. In addition,
ketones in water,7 we began to investigate the aforemen-
milder reaction conditions and higher efficiency are also
tioned challenging problem with our newly developed irid-
highly demanded.
ium catalysts. We envision that a directing group (DG) may
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be necessary to direct good site-selectivity while maintain-
7
TC-2
TC-4
TC-5
TC-6
TC-7
TC-8
TC-9
TC-10
LC-1
LC-2
LC-3
TC-3
TC-3
100,000
100,000
100,000
100,000
100,000
100,000
100,000
100,000
100,000
100,000
100,000
100,000
100,000
5,000
25
>99
>99
>99
>99
>99
>99
>99
>99
31[d]
50[d]
41[d]
>99
>99
>99
240,000
200,000
240,000
200,000
200,000
150,000
150,000
240,000
20,670
33,330
ing a broad scope for the hydroxyl groups.8 If the directing
group itself is also an activating group,9 we may be able to
achieve high efficiency under mild conditions. Herein, by
using 4-(N-substituted amino) aryl as the directing and ac-
tivating group, a wide scope of alcohols (primary, second-
ary, and tertiary) are easily deoxygenated in water, with ex-
tremely high site-selectivity and efficiency (Scheme 1c).
The directing group can either undergo further transfor-
mations,9c,d,10 or remain a sub-structure of drug candidates
(Scheme 1d).11
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7
8
8
30
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25
10
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30
30
12
40
40
25
13
14
15
90
90
90
60
>180
120
9
16
17
18[e]
19[e,f]
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27,330
2. Results and Discussion
100,000
33,000
2.1 Reaction condition optimization
20[e,g] TC-3
2,500
Initial directing-group screening revealed that N,N-
dimethylaminophenyl could induce the deoxygenation
(see Tables S1 and S2 in SI). With this in hand, the
1
[a] Conversions obtained by H NMR analysis of the crude reaction
mixtures, and deoxygenated product was identified. During this
course, dehydration product appeared, but it was quickly converted
to 2a completely. [b] Isolated yield after column chromatography. [c]
condition
optimization
commenced
with
the
deoxygenation of secondary alcohol 1a (Table 1). Catalyst
TC-3 showed excellent catalytic activity (entries 1-4). Even
at 100,000 S/C ratio, the deoxygenation was completed
within 25 min (TOF = 240,000 h-1), and product 2a was
isolated in 92% yield (entry 4). Increasing the S/C ratio to
500,000 led to various byproducts (entry 5). Further
screening of our other catalysts (TC-1, TC-2, and TC-3 to
TC-10) at 100,000 S/C ratio also gave satisfactory results,
with the deoxygenation completed within 25-40 min and
TOF values ranging from 150,000 to 240,000 h-1 (entries 6-
14). We also explored related Li’s catalysts (LC-1 to LC-3)
and found that they did not give satisfactory results
(entries 15-17).12 Reducing the formic acid amount or
lowering the temperature decreased the efficiency (entries
18-20). At 100,000 S/C ratio, organic solvents such as
acetonitrile, dichloroethane, acetone, and ethanol did not
afford any deoxygenated products.
1
TLC indicated lots of starting material. [d] H NMR conversion with
1,3,5-trimethoxybenzene as internal standard, and 1a was observed in
considerate amount. [e] HCOOH (2 equiv.). [f] At 60 oC. [g] At room
temperature.
2.2 Directing group screening
We then examined different related activating groups
(Table 2). Surprisingly, 2-(N,N-Dimethylamino)phenyl (G2)
or 3-(N,N-dimethylamino)phenyl (G3) could not induce the
deoxygenation, even at much lower 1000 S/C ratio. On the
other hand, 4-(N,N-diethylamino)phenyl (G4), 4-
(pyrrolidin-1-yl)phenyl (G5), 4-(piperidin-1-yl)phenyl (G6),
and 4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl (G7) were
all effective activating groups. The reaction of (3,4-
dihydroquinolin-1(2H)-yl)phenyl (G8) derivative 1b-7 gave
messy products. 4-(N-Methylamino)phenyl (G9), with a N-
H bond, also served as good activating group. The
deoxygenation of 4-acetamidophenyl (G10) derivative 1b-9
Table 1. Optimization of the reaction conditions.
required
hexafluoroisopropanol.
Table 2. Screening of directing groups.
lower
S/C
ratio
and
addition
of
Time
(min)
5
TOF
(h-1)
Conversion
(%)[a]
entry Cat.
S/C
1
TC-3
TC-3
TC-3
TC-3
TC-3
TC-1
10,000
20,000
50,000
>99
120,000
120,000
200,000
240,000
-
[a] TLC indicated compete conversion. [b] Isolated yields. [c] S/C =
1000. [d] Complex mixture obtained. [e] HFIP-H2O (1:1, v/v) as solvent.
2
3
4
5
6
10
>99
15
>99
>99 (92)[b]
2.3 Further lower S/C ratios, gram-scale reaction, and pH-
efficiency correlation
100,000 25
[c]
500,000
100,000
30
25
-
>99
240,000
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Deoxygenation of 1b at much higher 500,000 and
1,000,000 S/C ratios under nitrogen atomsphere in
degassed water afforded 89% and 87% yields, respectively
(Table 2, 2b). The TOF values were 445,000 h-1 in the
former and 435,000 h-1 in the latter. A gram-scale reaction
was completed within 1 h at 100,000 S/C ratio, giving 2b in
80% yield.
1
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3
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7
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9
The correlation between initial pH values and yields
were studied (Table 3), using the reaction of 2b at 100,000
S/C ratio as a model. The initial pH values were obtained
by tuning the molar ratios of HCOOH and HCOONa (see
Table S4 in SI). The highest efficiency was obtained under
acidic condtions (pH = 1.6), and the efficiency dropped
when the initial pH values of the reaction media was
increased. This indicates that formic acid served as not
only hydride donor but also reaction promotor.
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Table 3. Correlation between initial pH values and yields
pHa
Yield (%)b
1.6
92
3.0
70
3.5
68
3.9
50
4.4
32
7.2
1
[a] Initial pH values of the reaction media. [b] Determined by 1H NMR
of the crude reaction mixture.
2.4 Substrate scope and fuctionality tolerance studies
By using 4-N,N-dimethylaminophenyl (G1) as the
directing group, a variety of primary and secondary
alcohols was submitted to the optimal conditions, and the
functionality tolerance was examined (Table 4). Primary
alcohols 1c, 1d, 1e, and 1f were readily deoxygenated.
Secondary alchohols (1g-k) with different kinds of aliphatic
chains were also susceptible to the deoxygenation. In these
cases,
the
addition
of
trifluoroethanol
or
hexafluoroisopropanol was essential. It is worth noting
that electron-rich alkenyl group in 1k was well compatible.
Alcohols with both electron-rich (1l-t) and electron-
deficient (1u-1ae) aryls gave yields ranging from 80% to
96%. In these cases, different kinds of funcitonal groups on
the aryl rings, for example, alkyl, aryl, halogen,
trifluoromethyl, ester, cyano, and nitro, were well tolerated.
Fused or heteroaryls (1af, 1ag, 1ah, 1ai, 1aj, 1ak, 1al, 1am),
showed almost no inhibitation against the deoxygenation
(74-99% yields); they all surrived well from the acidic
conditions, even though the azaryls are basic or acid-
sensitive. Di-deoxygenation of diol 1an also occurred
feasibly. Good tolerance of active benzylic heteroatoms
(1ao, 1ap, and 1aq) was also observed. Under the
deoxygenation conditions, the alkynyl group in 1ar stayed
intact. Desired product 2as was isolated in 76% yield,
together with undersired hydrogenated product 2j in 19%
yield, from the reactions of 3-phenylprop-2-en-1-ol (1as).
[a] Reactions on 0.25-mmol scale. [b] TLC indicated compete
conversion. [c].Isolated yields. [d] S/C = 1000 in HFIP-H2O (1:1, v/v).
[e] S/C = 20,000 in TFE-H2O (1:1, v/v).
Tertiary alcohols with directing groups were also easily
deoxygenated at 1000 S/C ratio in water-fluoro alcohol
mixed solvents (Table 5). Structurally diverse alcohols (3a
to 3f) all gave rise to excellent yileds (> 94%). The
cyclopropyl with high ring-strain did not undergo ring
expansion
(4c).
Exhilaratingly,
the
4-(N,N-
dimethyl)phenyl directed deoxygenations of cycloalkanols
(3g to 3k) occurred exclusively, with the corresponding
products isolated in 98-99% yields. The ring strain in
different sizes of cycles did not cause ring-opening or
dehydration products. Based on these results, the
modifications of a series of ketones via Grignard-type
arylation and subsequent deoxygenation were performed.
The structral modifications of xanthone, 1-tetralone and 2-
adamantanone with our deoxygenation strategy gave the
corresponding products 4l, 4m, and 4n in excellent yields.
Naturally occurring camphor, (S)-carvone, and (R)-
muscone also successfully underwent the modification,
generating 4o, 4p, and 4q in 99%, 96%, and 99% yields,
respectively. Notably, the endocyclic C=C bond of 3p was
hydrogenated, and four stereoisomers were obtained; cis-
or trans-3q derived from muscone delivered the same
Table 4. Deoxygenation of primary and secondary alcohols.[a]
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results. Dipfluzine, a calcium antagonist,13 was modified
into 4r in 97% yields within 60 min.
Table 5. Deoxygenation of tertiary alcohols.[a]
intermediates by dehydroxylation of alcohols. However,
the in situ C NMR did not detect the carbocation signal
13
1
2
3
4
5
6
7
8
(see Figures S2 and S3 in SI), while the ESI-HRMS analyses
of alcohols 1 and 3 demonstrated their strong proclivity to
form carbocations (see Figures S4-S6 and realted HRMS
data in Section 9.6 in SI). Deoxygenations with HCO2H in
D2O (Conditions A) and with DCO2H in water (Conditions
B) showed that the installed hydrogen majorly came from
the formyl hydrogen of formic acid.
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[a] Reactions on 0.25-mmol scale. [b] TLC indicated compete
conversion. [c] Isolated yields. [d] Water as the sole solvent. [e] S/C =
100,000. [f] HFIP-H2O (1:1, v/v) as solvent.
The current deoxygenation protocol is also highly
site-selective. As shown in Table 6, only the hydroxyl
adjacent to the directing group could be deoxygenated.
The phenolic hydroxyls (1at) kept intact. Other
alcoholic hydroxyls, no matter primary (1au, 3s),
secondary (3t), or tertiary (3u), were not affected.
Surprisingly, even exposed to highly reductive species,
ketone group (3u) was immune. This is of high
importance in the modification of some hydroxyl- or
ketone-containing natural products.
Scheme 2. Mechanistic studies
The plausible mechanism is shown in Scheme 3. On one
hand, iridium chlorides react with formic acid to generate
iridium hydrides B through active catalyst iridium
formates A.7 The formation of iridium hydrides was
spectrally demonstrated in our previous work via 1H
NMR.7a One the other hand, in the acidic conditions
alcohols 1 or 3 are converted to carbocations C, which are
Table 6. Selective deoxygenation of diols, ketoalcohols, and
phenolic alcohols
stabilized by the 4-(N,N-dialkyl)phenyl groups or the
5f,14
added fluorous alcohols.
Without the fluoroalkanol
cosolvents, dehydration products alkenes were observed in
the reactions of tertiary alchols 3. The carbocations C are
highly stabilized by the strongly electron-donating 4-(N,N-
dialkkylamino)aryl group via the resonant iminium cation
form D. Under the standard conditions, other less
electron-donating groups such as 2,4,6-trimethoxyphenyl,
4-methoxyphenyl, 4-hydroxyphenyl, fur-2-yl, or thiopen-
2-yl did not work (see Tables S1 and S2 in SI). The masked
carbocations D are highly electrophilic, and react fast with
iridium hydrides B to give deoxygenated products 2 or 4,
and regenerate active catalysts A. In the kinetic isotope
effect (KIE) studies (Scheme 2c), primary KIE was observed
(kH/kD = 2.63, eqn. 4), implying that the generation of
iridium hydrides B (step b, cleavage of C-H/D bond) is
probably the rate-determining step. Secondary KIE was
also observed (kH/kD = 1.25, eqn. 5), suggesting that the
deoxygenation follows a SN1-type pathway. This is in high
accordance with the proposal of carbocation intermediates.
The H/D ratios in Conditons A and B in Scheme 2 are
atributed to the H–D exchanges in [Ir]H–D2O and in [Ir]D–
H2O, respectively.7a
[a] TLC indicated compete conversion. [b].Isolated yields. [c]
Water as solvent, S/C = 100,000. [d] TFE-H2O (1:1, v/v) as solvent,
S/C = 20,000. [e] d.r. of 3t is 70:30. [f] Two-step yield.
2.5 Mechanistic studies
Mechanistic studies were performed (Scheme 2). In the
absence of iridium catalysts, treating alcohol 3i in water
with formic acid gave dehydration product 5 via E1
elimination (eqn. 1), while treating 1b in the presence of a
thiol delivered sulfide 6 via SN1 substitution (eqn. 2). These
two reactions pointed to the formation of carbocation
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ACS Catalysis
Further transformation of the directing group was
demonstrated in Scheme 5. Methylation of the N,N-
dimethylamino group of 4l yielded
aryltrimethylammonium 12. Palladium-catalyzed Kumada-
type coupling of 12 gave 14 in 94% yield, while Nickel-
catalyzed Suzuki-type coupling produced 16 in 83% yield.
1
2
3
4
5
6
7
8
9
10
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12
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Scheme 3. Proposed Mechanism.
2.6 Structural modifications of steroids and further
Transformations of the directing group
Structural modifications of steroid compounds often
give potential new bioactive compounds.15 We performed
the structural modifications of pasterone (7a), estrone (7b),
and epiandrosterone (7c), by installment of 4-
piperidylphenyl and subsequent deoxygenation (Scheme
4). Only one diastereomer was isolated, and the
stereochemistry was assigned by NOE studies. The
phenolic and secondary alcoholic hydroxyls remained
intact through the two-step sequence. Similarly,
cholesterol (9) could also be modified into 11 by Dess-
Martin oxidation, directing group installation, and our
iridium-catalyzed deoxygenation, through intermediates
10 (dr. > 20:1).16 Again, very good diastereoselectivity (dr. >
20:1) was observed in the deoxygenation. The Grinard
reaction favourably took place at the sterically smaller α-
face opposite to the 10-methyl. We assume that the hydride
installation with sterically bulky iridium hydride
preferentially occurred at the sterically less convex β-face
of the resultant carbocation, to avoid the steric congestion
between G1 and 10-methyl. In other words, it was the
installed G1 group that reversed the facial selectivity. Smilar
stereochemical outcome in the deoxygenation of 3-
methylcholesterol was also reported by Ireland and
coworkers.3i
Scheme 5. Transformations of the directing group
3. Conclusion
In conclusion, we have developed an iridium-catalyzed
highly efficient and site-selective deoxygenation of alco-
hols, under the assistance of an N-(substituted amino)aryl
directing group. A number of structurally diverse primary,
secondary, and tertiary alcohols, adjacent to the directing
group, can be deoxygenated with excellent functionality
tolerance, in excellent yields, and with extremely high effi-
ciency (S/C up to 1,000,000, TOF up to 445,000 h-1). The
alcoholic hydroxyls at other positions, no matter primary,
secondary, or tertiary, are not affected. The reaction con-
ditions are very mild (in water and open air), and formic
acid is used as both promoter and hydride donor. The KIE
studies reveal that hydride generation is the rate-deter-
mining step, and the deoxygenation follows an SN1-type
pathway. The application of the deoxygenation protocol
has been demonstrated in the structural modification of
complex ketones and steroids.
ASSOCIATED CONTENT
Supporting Information. Further directing group screening,
detailed experimental procedures, analytic data of prepared
alcohols and products, copies of 1H, 13C, and NOE NMR spectra
of products, and 1H NMR spectra of the reaction mixtures.
AUTHOR INFORMATION
Corresponding Author
* zhyang@mail.buct.edu.cn (Z. Y.)
* jxxu@mail.buct.edu.cn (J. X.)
ORCID
Zhanhui Yang: 0000-0001-7050-8780
Jiaxi Xu: 0000-0002-9039-4933
Notes
The authors declare no competing financial interest.
Scheme 4. Modification of steroid compounds.
ACKNOWLEDGMENT
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Catalyzed Chemoselective Defunctionalization of Ether‐
Containing Primary Alkyl Tosylates with Hydrosilanes. Angew.
Chem., Int. Ed. 2017, 56, 3389-3391. (i) Ireland, R. E.; Muchmore,
We thank the National Natural Science Foundation of China
(No. 21602010 to Z. Yang), and the BUCT Fund for Discipline
Construction and Development (Project No. XK1533, to Z.
Yang) for financial support.
1
2
3
4
D.
C.;
Hengartner,
U.
N,
N,
N’,
N’-
Tetramethylphosphorodiamidate Group. A Useful Function for
the Protection or Reductive Deoxygenation of Alcohols and
Ketones. J. Am. Chem. Soc. 1972, 94, 5098-5100.
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