Mitsunobu Reactions Catalytic in Phosphine and a Fully Catalytic System

Article abstract of DOI:10.1002/anie.201506263

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance, but has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichiometric phosphine oxide and hydrazine by-products that complicate purification. A catalytic Mitsunobu reaction using innocuous reagents to recycle these by-products would overcome both of these shortcomings. Herein we report a protocol that is catalytic in phosphine (1-phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchi's azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction. Make it catalytic: A catalytic Mitsunobu reaction using innocuous reagents to recycle the stoichiometric phosphine oxide and hydrazine by-products was developed. The reported method is catalytic in 1-phenylphospholane and uses phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchi's azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction.

Full text of DOI:10.1002/anie.201506263

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506263
German Edition: DOI: 10.1002/ange.201506263
Organocatalysis
Mitsunobu Reactions Catalytic in Phosphine and a Fully Catalytic
System
Joseph A. Buonomo and Courtney C. Aldrich*
Abstract: The Mitsunobu reaction is renowned for its mild
reaction conditions and broad substrate tolerance, but has
limited utility in process chemistry and industrial applications
due to poor atom economy and the generation of stoichio-
metric phosphine oxide and hydrazine by-products that
complicate purification. A catalytic Mitsunobu reaction using
innocuous reagents to recycle these by-products would over-
come both of these shortcomings. Herein we report a protocol
that is catalytic in phosphine (1-phenylphospholane) employ-
ing phenylsilane to recycle the catalyst. Integration of this
phosphine catalytic cycle with Taniguchiꢀs azocarboxylate
Scheme 1. Proposed catalytic Mitsunobu reaction.
catalytic system provided the first fully catalytic Mitsunobu
reaction.
T
he Mitsunobu reaction is the displacement of an alcohol
ment and optimization of a Mitsunobu reaction catalytic in
phosphorus utilizing dibenzophosphole and phospholane
precatalysts 1 and 2 (Scheme 1B), inspired by the develop-
ment of the catalytic Appel,[10a] Staudinger,[10b] and Wittig[11]
reactions. We then combined this catalytic cycle with the
Taniguchi iron–phthalocyanine catalytic system to generate
the first fully catalytic Mitsunobu reaction (Scheme 1A).
Chemoselective reduction of the phosphine oxide product
back to the phosphine in the presence of a reactive azo
compound is required in order to complete the phosphine
catalytic cycle. We initially investigated dibenzophosphole
oxide 1 as a precatalyst due to its facile reduction by silanes
and its ability to tune the catalyst through modification of the
aryl rings.[10] The coupling of 4-nitrobenzoic acid and benzyl
alcohol or 4-trifluoromethylbenzyl alcohol was studied with
À
with a pronucleophile (Nu H) mediated by phosphine and
azocarboxylate reagents, which work in concert to activate
the pronucleophile through deprotonation and convert the
alcohol to
a
reactive alkoxyphosphonium species.[1]
Renowned for its mild reaction conditions and broad
substrate tolerance, the Mitsunobu reaction is capable of
[2]
À
À
À
À
À
forming C O, C N, C S, C X, and C C bonds. However,
the Mitsunobu reaction is highly underutilized in process
chemistry and manufacturing due to arduous purification
from by-products and poor atom economy.[3] Although
several innovative reagents have been developed that can
be removed by liquid–liquid or solid–liquid extractions to
facilitate purification,[4] the ideal Mitsunobu reaction would
be catalytic in phosphine and azocarboxylate, and use
innocuous reagents to recycle these catalysts.[5] Toward this
goal, Toy and co-workers rendered the Mitsunobu catalytic in
the azocarboxylate using PhI(OAc)2 to oxidize the hydrazine
by-product[6] whereas Taniguchi and co-workers developed an
iron(II) phthalocyanine catalytic system employing oxygen as
the terminal oxidant.[7] OꢀBrien and co-workers disclosed the
first example of a Mitsunobu reaction that is catalytic in
phosphine in the patent literature,[8] and optimization of this
reaction is heavily desired.[4,9] Herein we report the develop-
a
model system employing stoichiometric DIAD,
1 (10 mol%), and various silanes (Table 1). To benchmark
these results, the yield obtained with stoichiometric triphe-
nylphosphine (TPP) was determined as 84% (Table 1,
entry 1). Polymethylhydrosiloxane and triphenylsilane did
not provide catalytic turnover (Table 1, entries 3 and 4).
Diphenylsilane (entry 5) provided the first encouraging yield
of 42%, whereas phenylsilane (entry 6) furnished an
improved yield of 63%. We next explored the impact of
PhSiH3 stoichiometry (entries 8–11; see also Table S2) on the
outcome of the reaction. We observed that excess silane was
detrimental, although it led to faster conversion. Conversely,
a lower amount of silane led to substantially slower con-
version, but did result in slightly improved yields. As a control,
we also measured the background reaction in the absence of
PhSiH3 confirming its vital role (entry 8). The reaction of
PhSiH3 with alcohols in the presence of Lewis acids (i.e., 4-
nitrobenzoic acid) at elevated temperatures is precedented[12]
and contributed to the lower yields (Figure S1). Thus, even
the yield of the stoichiometric TPP reaction was reduced from
84% to 77% when PhSiH3 was included in the reaction
[*] J. A. Buonomo, Dr. C. C. Aldrich
Department of Medicinal Chemistry, University of Minnesota
308 Harvard St. SE, Minneapolis, MN 55455 (USA)
E-mail: aldri015@umn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506263.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited and is not used for commercial purposes.
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Table 1: Development of conditions for the Mitsunobu reaction catalytic
Reduction of 2 was facile, even at 258C, as evident of its
low DG° of 14.1 Æ 0.4 kcalmolÀ1. Whereas 1 was significantly
less reactive with a DG° of 21.3 Æ 3.6 kcalmolÀ1 and was not
reduced at 258C even after 120 h. These data would indicate
that the catalytic Mitsunobu reaction should readily occur at
room temperature with 2. Unfortunately, this is not true in
practice and the catalytic Mitsunobu reaction requires
elevated temperatures to achieve complete conversion. The
activation energies were determined in the absence of other
reagents (pronucleophile, alcohol, and DIAD), which attenu-
ate the rate of phosphine reduction (Table S7).
in phosphine.[a]
Entry
R
[P]
x
Silane
y
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
CF3
CF3
CF3
CF3
H
H
H
H
TPP
TPP
1
1
1
1
1
1
1
1
1
2
2
2
2
110
110
10
10
10
10
10
10
10
10
10
10
5
none
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3a
3a
3a
3a
84
77
0
PhSiH3
PHMS
Ph3SiH
Ph2SiH2
PhSiH3
none
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
1.1
1.5
2.0
1.1
1.1
–
0.5
1.5
3.0
6.0
1.1
1.1
1.1
1.1
0
42
63
0[c]
66[d]
63
52
43
77
77[e]
58[f]
54[g]
With the optimal catalytic conditions established, we then
investigated the substrate scope with a range of alcohols and
pronucleophiles (Table 2). For comparison, the yields of the
stoichiometric reaction conducted at room temperature are
also presented. Primary benzylic, allylic, and alkyl alcohols
(Table 2, entries 1–5) were reacted with 4-nitrobenzoic acid to
afford the corresponding esters in moderate to good yields.
The lower yield of the benzylic substrates, relative to the
stoichiometric reaction, is due to competitive silane reactivity
of the alcohols (Figure S1). Notably, the 82% yield obtained
with the simple alkyl alcohol, 3-(4-fluorophenyl)propanol
(entry 5) was identical to the stoichiometric version. Prop-
argyl alcohol was also esterified with 84% yield (entry 6),
similar to its stoichiometric counterpart. Secondary alcohols
were also competent substrates (entries 7 and 8) providing
respectable yields with high enantiomeric purities (e.r. >
94:6). We next examined the coupling of 2-phenylethanol
with benzoic acid, aminoacid, phenol, and sulfamide pronu-
cleophiles (entries 9–12). These substrates all afforded the
corresponding products in good to excellent yields compared
to the stoichiometric reaction. Intramolecular reaction of
Boc-protected homoserine furnished the g-lactone in an
impressive 87% yield (entry 13). The background reaction
without the phosphine catalyst was less than 2%. Reaction of
2’,3’-O-isopropylideneinosine with Boc-protected sulfamide
provided the coupled product in 70% yield (entry 14) high-
lighting the utility of the catalytic Mitsunobu reaction with
more challenging substrates.[14]
Integration of the phosphine and azocarboxylate catalytic
cycles would provide the first fully catalytic Mitsunobu
reaction. Given the opposing requirements for catalyst
turnover (phosphine oxide reduction versus hydrazine oxida-
tion), it was unclear whether these two cycles would be
compatible. Among the two described azocarboxylate cata-
lytic systems,[6,7] we chose the Taniguchi iron(II) phthalocya-
nine [Fe(pc)] protocol that utilizes catalytic hydrazine 4,
because it employs oxygen as the terminal oxidant. As a proof
of concept, we studied the coupling of 4-methoxybenzyl
alcohol[15] with 4-nitrobenzoic acid. Our first attempt of
employing our optimized protocol with Taniguchiꢀs condi-
tions (10 mol% [Fe(pc)], 10 mol% 4) furnished a 15% yield
(Table 3, entry 1). While not impressive, this result indicated
that both catalytic cycles could be combined as at least one
turnover was noted. Performing the reaction under an
oxygen-enriched atmosphere quickly improved the yield
from 15 to 35% (Table 3, entries 1 and 3). Switching to 5 Š
molecular sieves slightly improved yields; however, combin-
ing an oxygen-enriched atmosphere with 5 Š molecular sieves
9
10
11
12
13
14
15
2
1
[a] Reactions performed on 1 mmol scale at 0.25m. [b] Isolated average
of two reactions. [c] Reactions with the reduced form of 1 without silane
added produced 7% of product. [d] 46 h. [e] Reaction at 10 mmol scale
was performed with 78% yield. [f] 38 h. [g] 69 h.
(entries 1 and 2). Based on these considerations, we settled on
1.1 equivalents of PhSiH3 as optimal, to minimize both
reaction time and undesired reactivity. Finally, we evaluated
phospholane precatalyst 2 using our optimized conditions and
were elated to obtain 77% yield (entry 12), which is identical
to the stoichiometric TPP version under the same conditions.
The catalyst loading could be lowered to 5 mol% without
affecting the yield, with 1 mol% of catalyst still providing
a respectable 54% yield (entries 12–15).
We speculated that the greater reactivity of catalyst 2 was
due to its more facile reduction by PhSiH3, which is the rate-
limiting step in the phosphine catalytic cycle. The group of
van Delft had indicated that 1 and 2 were nearly equivalent in
reactivity as measured by reduction with Ph2SiH2 at 1008C in
1,4-dioxane.[10] To study the relative reactivity of 1 and 2 more
rigorously, we measured their rates of reduction by 31P NMR
spectroscopy under pseudo first-order conditions (30, 15,
7.5 equiv PhSiH3) at various temperatures ranging from 25 to
808C.[12] The activation energies (DG°) were then calculated
from the temperature dependence of the second-order rate
constants using Arrhenius (Figure 1) and Eyring plots.
Figure 1. The Arrhenius plots of 1 and 2.
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Chemie
Table 2: The substrate scope of the catalytic Mitsunobu reaction.[a]
Table 3: The initial optimization of the fully catalytic Mitsunobu
reaction.[a]
Entry Product
Catalytic Stoichiometric
yield [%][b] yield [%][b,c]
Entry
R
[P]
MS [Š][b]
Atmosphere
Yield[c]
1
2
3
4
5
6
7
8
3a 77
94
1
2
3
4
5
6
OMe
OMe
OMe
OMe
OMe
H
1
1
1
2
2
2
4
5
5
5
5
5
air
air
15
19
35
35
63[e]
68
O2 enriched[d]
air
3b 76
3c 61
3d 50
3e 82
3 f 84
3g 69[d]
3h 68[e]
92
O2 enriched[d]
O2 enriched[d]
80
[a] Reactions performed on 0.5 mmol scale at 0.17m employing
1.5 equivalents of 4-nitrobenzoic acid. [b] All MS are powdered.
[c] Average yield of the isolated product of two reactions. [d] Oxygen
prepared by the reaction of NaOCl and H2O2. [e] Average yield of the
isolated product of three reactions ranging from 60–68% yield.
50
82
proved to be crucial and increased the yield to 63% (entry 5),
which is comparable to the yield obtained with our catalytic
phosphine conditions alone (Table 2, entry 3). As noted
before, catalyst 2 was superior to catalyst 1 in the fully
catalytic Mitsunobu reaction (Table 3, entries 3 and 5).
We were able to successfully combine Taniguchiꢀs
approach with our novel catalytic phosphorus methodology.
Both the phosphorous catalyst and the catalytic hydrazine can
also be recovered easily in greater than 95% quantities during
chromatography. Fe(pc) is nontoxic and inexpensive, and 2 is
synthesized in only two steps without the need for halogen-
ated solvents or carcinogenic butadiene.[11b,16] While there is
still room for improvement, the concept of a fully catalytic
Mitsunobu reaction has finally been realized. Improvements
in yield and reaction setup will turn this concept into a more
practical application, but this reaction still fulfills the require-
ments of a sustainable, safe, and economic Mitsunobu
reaction for process chemistry and manufacturing. We are
currently engaged in seeking improvements to our method-
ology with new catalysts.[17] We are also seeking a fully
catalytic Mitsunobu reaction that is feasible at room temper-
ature[18] to ensure the widest possible application of this
powerful transformation.
90
77[d]
78[e]
9
3i 76
96
10
11
12
13
3j 63
83
3k 51[f]
3l 72
85[f]
90
3m 87[g,h]
98[g]
Experimental Section
14
3n 70[i]
93[i]
Typical procedure for the Mitsunobu reaction catalytic in phosphine:
To a 15 mL pressure tube equipped with a stir bar was added catalyst
2 (18 mg, 0.10 equiv, 0.10 mmol) and 4-nitrobenzoic acid (250 mg,
1.5 equiv, 1.5 mmol). Then, THF (4 mL) was added followed by
benzyl alcohol (103 mL, 1.0 equiv, 1.0 mmol), DIAD (216 mL,
1.1 equiv, 1.1 mmol), and phenylsilane (135 mL, 1.1 equiv, 1.1 mmol).
The reaction vessel was sealed with a #15 O-ring and heated to 808C
for 18 h. The reaction was cooled to 238C and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy eluting with hexane (to recover reduced 2) followed by a step-
wise gradient from 0 to 10% EtOAc in hexane. Benzyl 4-nitro-
benzoate was isolated as an off-white solid (197 mg, 0.77 mmol,
77%).
[a] Reactions performed on 0.5–1.0 mmol scale at 0.25m employing
1.5 equiv of pronucleophile, 10 mol% loading of catalyst 2, and
1.1 equivalents of both DIAD and PhSiH3. Reactions were all run at 808C.
[b] Isolated average of two reactions. [c] Reactions performed at 238C
with 1.5 equivalents of pronucleophile, TPP, and DIAD without phenyl-
silane for 18 h. [d] e.r. 94:6. [e] e.r.>99.5:0.5. [f] 48 h. [g] Concentration
was 0.04m. [h] Background reaction with only Boc-homoserine-OH,
DIAD, and PhSiH3 only produced traces. [i] N-Boc sulfamide (3 equiv)
was used as the pronucleophile.
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Typical procedure for the fully catalytic Mitsunobu reaction: To
a 35 mL pressure tube equipped with a stir bar was added catalyst 2
reactions, see: c) J. An, R. M. Denton, T. H. Lambert, E. D.
Nacsa, Org. Biomol. Chem. 2014, 12, 2993 – 3003.
(9.0 mg, 0.10 equiv, 0.05 mmol), catalyst
4
(12.5 mg, 0.10 equiv,
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2012.
0.05 mmol), Fe(pc) (28.5 mg, 0.10 equiv, 0.05 mmol), 4-nitrobenzoic
acid (125 mg, 1.5 equiv, 0.75 mmol), and 5 Š powdered molecular
sieves (500 mg). THF (3 mL) was added followed by 4-methoxyben-
zyl alcohol (62 mL, 1.0 equiv, 0.50 mmol), and phenylsilane (68 mL,
1.1 equiv, 0.55 mmol). The vessel was purged with oxygen gas and
sealed with a #15 O-ring. The reaction was heated at 708C for 48 h.
The reaction was cooled to 238C, filtered to remove the sieves and the
filtrate was partitioned between EtOAc (30 mL) and saturated
aqueous NaHCO3 (30 mL). The organic layer was separated and
washed with saturated aqueous NaCl (30 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography eluting with hexane (to recover reduced 2
and oxidized 4) followed by a step-wise gradient from 0 to 10%
EtOAc in hexane. 4-Methoxybenzyl 4-nitrobenzoate was isolated as
a yellow solid (90.5 mg, 0.32 mmol, 63%).
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Acknowledgements
We thank the National Science Foundation for primary
support of this work (pre-doctoral fellowship to Joe Buo-
nomo, GRFP-ID: 00039202). We thank Christopher D.
Brown for acting as a “checker” to confirm reproducibility
of reaction results.
[13] See the Supporting Information for details.
[14] Competitive intramolecular cyclization through attack of the
purine N-3 nitrogen on the activated 5’-alcohol results in
cyclonucleoside formation, a well-known side reaction that can
plague Mitsunobu couplings, which we thought could be
exacerbated at the elevated reaction temperatures required for
the catalytic Mitsunobu reaction.
Keywords: organocatalysis · phosphorus heterocycles ·
reaction kinetics · silanes · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13041–13044
Angew. Chem. 2015, 127, 13233–13236
[15] p-Methoxybenzyl alcohol was selected for our model studies
because in 1H NMR spectroscopy the methoxy group at 3.76
undergoes a diagnostic chemical shift to 3.91 in the ester product
that allows easy monitoring by 1H NMR spectroscopy.
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Received: July 7, 2015
Published online: August 17, 2015
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