Recyclable mitsunobu reagents: Catalytic mitsunobu reactions with an iron catalyst and atmospheric oxygen

Article abstract of DOI:10.1002/anie.201300153

Aerobic recycling: A catalytic amount of a hydrazine reagent is sufficient to promote Mitsunobu reactions in the presence of triphenylphosphine, an iron catalyst, and air. The active form of the catalyst, an azo species, can be readily generated by iron-c

Full text of DOI:10.1002/anie.201300153

Angewandte
Chemie
DOI: 10.1002/anie.201300153
Synthetic Methods
Recyclable Mitsunobu Reagents: Catalytic Mitsunobu Reactions with
an Iron Catalyst and Atmospheric Oxygen**
Daisuke Hirose, Tsuyoshi Taniguchi,* and Hiroyuki Ishibashi
In 1967, Mitsunobu and co-workers reported that a combina-
tion of diethyl azodicarboxylates (DEAD; 3) and triphenyl-
phosphine causes condensation reactions between alcohols
and acids (phosphoric acids or carboxylic acids) to give the
corresponding esters.[1] Notably, when chiral secondary alco-
hols are used in this reaction, ester products are provided with
inversion of the stereochemistry.[2] Moreover, various nucle-
ophiles, such as phenols, sulfonyl amines, azide, thiols, and
activated methylenes, can be used instead of carboxylic acids,
although the reactivity depends on the acidity of nucleo-
philes.[2] Owing to these characteristic and mild reaction
conditions, the Mitsunobu reaction has been established as
one of the most useful tasks in synthetic chemistry. However,
there are significant problems with using DEAD, including
high toxicity, explosion risk, and difficulty in removal of the
resultant hydrazine waste (diethyl 1,2-hydrazinedicarboxy-
late) after the reaction. Because of these drawbacks, and the
problem of phosphine reagent waste, synthetic chemists in
fields of process chemistry or manufacturing hesitate to use
the Mitsunobu reaction. Therefore, several substituted
reagents and modified methods to avoid these problems
have been reported.[2,3] In this regard, obviously, reducing azo
reagents to a catalytic amount with the aid of safe and
inexpensive stoichiometric oxidants is a significant improve-
ment in the Mitsunobu reaction.[4] In 2006, Toy and co-
workers succeeded in reducing the amount of DEAD to
a catalytic amount (10 mol%) using iodobenzene diacetate
[PhI(OAc)2] as a reoxidizer.[5] This is the only example of
a catalytic (in azo reagents) Mitsunobu reaction to date.[6]
Recently, we reported the generation and reactions of
alkoxycarbonyl radicals with FeII(Pc)-catalyzed (Pc = phtha-
locyanine) aerobic oxidation of carbazates (RCO2NHNH2).[7]
Inspired by this result, we conceived the iron-catalyzed
aerobic reoxidation of diethyl 1,2-hydrazinedicarboxylate
(1) to DEAD (3). Unfortunately, however, exposure of
hydrazine 1 to air in the presence of a catalytic amount of
Fe(Pc) gave no product [Equation (1)].[8] This is not a surpris-
ing result, as nitrogen atoms masked by electron-drawing
ethyl carbonates, unlike alkyl or aryl hydrazines, are unreac-
tive under normal aerobic oxidation conditions.[9] Next, we
turned to the reaction of ethyl 2-phenylhydrazinecarboxylate
(2), as we expected that a nitrogen atom adjoining a phenyl
group would be easily oxidized owing to stabilization of the
intermediary radical or cation by delocalization on the
aromatic ring.[10,11] Indeed, 2 was readily oxidized to the
corresponding ethyl 2-phenylazocarboxylate (4) under the
iron-catalyzed aerobic conditions. To our delight, the Mitsu-
nobu reaction between (ꢀ)-(S)-ethyl lactate (5) and 3,5-
dinitrobenzoic acid (6) proceeded in the presence of 4 and
triphenylphosphine to afford the corresponding ester product
with inversion of the stereochemistry [Equation (2)].
As 4 turned out to work as a Mitsunobu reagent, we
proposed a catalytic system that consists of iron-catalyzed
aerobic reoxidation of 2-arylhydrazinecarboxylate 8, as
shown in Scheme 1. 2-Arylazocarboxylate 9 promotes Mitsu-
nobu reactions in the presence of alcohols, carboxylic acids,
and triphenylphosphine to give ester products and 8. As 8
could be reoxidized to its azo form (9) by in situ iron-
catalyzed aerobic oxidation, 8 or 9 should work as a catalyst
for the Mitsunobu reaction with the aid of an iron catalyst and
air (oxygen) as a terminal oxidizer.[12] However, when
[*] D. Hirose, Dr. T. Taniguchi, Prof. Dr. H. Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharma-
ceutical and Health Sciences, Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
E-mail: tsuyoshi@p.kanazawa-u.ac.jp
[**] This research was supported by a Grant-in-Aid for Young Scientists
(B) (23790008) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300153.
Scheme 1. Concept for a catalytic Mitsunobu reaction.
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Table 1: Screening of hydrazine catalysts.
a mixture of alcohol 5, carboxylic acid 6, and triphenylphos-
phine in tetrahydrofuran (0.5m) was heated with catalytic
amounts (10 mol%) of Fe(Pc) and hydrazine 2 under air, the
desired ester product was not obtained at all (Scheme 2).
Entry
Catalyst
Yield [%][a]
e.r.
1
2
3
4
5
6
2, X=H
8a, X=F
8b, X=Cl
8c, X=Br
8d, X=NO2
8e, X=OMe
17
20
37
36
30
19
11:89
11:89
80:20
82:18
87:13
8:92
Scheme 2. An unsuccessful reaction.
Therefore, we decided to implement a reaction condition
screen (solvents, additives, concentration, and temperature;
see the Supporting Information). Fortunately, after several
preliminary experiments, we found that the addition of
molecular sieves (MS) triggered the reaction. A reaction in
the presence of activated 5ꢀ MS (470 mgmmolꢀ1) gave
product 7 in 17% yield, although with incomplete inversion of
stereochemistry (Table 1, entry 1).[13]
7
8
9
8 f, X=F
8g, X=Cl
8h, X=Br
25
53
48
94:6
94:6
92:8
Encouraged by this result, we decided to seek effective
hydrazine catalysts. First, the electronic effects of the func-
tional groups of ethyl 2-arylhydrazinecarboxylate 8a–e were
tested (Table 1, entries 2–6). It was revealed that hydrazine
catalysts with electron-withdrawing groups, such as halogens
(chloro and bromo) and a nitro group, gave the inversion
product 7 in a relatively high enantiomeric ratio, but the yield
was still low (entries 3–5). In contrast to these results,
hydrazine 8e, which has an electron-donating p-methoxy
group, did not improve the result (entry 6). Electron-deficient
aromatic rings seemed to be important for obtaining the
inversion product 7. On the other hand, hydrazine 8a, with an
electron-withdrawing fluorine substituent at the para posi-
tion, did not improve the result (entry 2). However,
m-fluorophenylhydrazine derivative 8 f gave inversion prod-
uct 7 in high selectivity (entry 7). The result for 8a is probably
due to an electron donation through the conjugated system,
rather than an inductive effect. Interestingly, both m-chlor-
ophenylhydrazine 8g and m-bromophenylhydrazine 8h pro-
vided inversion product 7 in better yield, and with high
selectivity (entries 8 and 9). The tuning of catalysts using
chlorine or bromine atoms seemed to be promising for
obtaining better results. Incidentally, o-halophenylhydrazine
catalysts 8i and 8j did not perform well, probably for steric
reasons (entries 10 and 11). Next, we tested the catalytic
activity of arylhydrazine derivatives bearing two chlorine
atoms. The 3,5-dichlorophenylhydrazine catalyst 8k afforded
almost the same result as 8g (entry 12), whereas 3,4-dichlor-
ophenylhydrazine catalyst 8l provided inversion product 7 in
the highest yield (79%) with almost perfect selectivity (e.r.,
98:2; entry 13). Although we have tested further combina-
tions of other halogens and positions, no catalyst superior to
8l was found. Replacement of the ethoxy group of 8l with
a cyclohexylamino group caused the disappearance of cata-
lytic activity (catalyst 8m; entry 14).
10
11
8i, X=F
8j, X=Cl
28
23
60:40
85:15
12
57
93:7
13
14
79
34
98:2
4:96
[a] Yield of isolated product.
The effects of minor changes from the optimized reaction
conditions are shown in Table 2. A significant drop in
reactivity was observed by replacing Fe(Pc) with other
catalysts such as tetraphenylporphyrin iron(III) chloride,
cobalt(II) phthalocyanine, copper(II) phthalocyanine, or
Manganese(II) phthalocyanine (Table 2, entries 2–5). When
the amount of Fe(Pc) was reduced to half, the yield of 7
somewhat decreased, and reducing the amounts of both
Fe(Pc) and 8l caused a further decline in the yield (entry 6).
When THF was substituted for a safer solvent, cyclopentyl
methyl ether (CPME),[14] lower yields and inversion ratios
were obtained (entry 7). Fortunately, reaction at a higher
temperature (908C) in CPME gave almost the same result as
that obtained with the standard conditions, and with shorter
reaction time (12 h; entry 7). As a notable result, we found
that this catalytic reaction proceeded at room temperature,
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usually improves the results in stoichiometric reactions.[16]
Table 2: Effects of changing reaction conditions.
Therefore, moderate reactivity is a limitation in this catalytic
method at present, and further improvement is a future
subject.
We would like to emphasize the advantageous character-
istics of hydrazine catalyst 8l. It was easily prepared in one
step (ethoxycarbonylation) from commercially available 3,4-
dichlorophenylhydrazine hydrochloride (see the Supporting
Information). A highly pure material was obtained by
recrystallization, and the crystalline solid was stable under
ambient conditions for more than one month. After the
reaction, we were able to almost completely recover hydra-
zine catalyst 8l in its azo form (96% yield), along with the
product, by silica gel chromatography.
In conclusion, we have developed a new catalytic method
for the Mitsunobu reaction. The most significant feature is
that ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate (8l)
can work as a good catalyst in air, which is an ideal terminal
oxidizer. Iron phthalocyanine, which complements this cata-
lytic system, is inexpensive and nontoxic, and is often used as
a pigment in food and clothing.[17] Although the current
reaction may not be perfect from the viewpoints of yield and
reaction conditions, this catalytic concept is innovative and
has significant potential. The combination of this concept with
modified phosphine reagents[2,6] has not yet been tested, but
we anticipate that it has promise for achieving a practical
Mitsunobu reaction. In short, the present reaction illustrates
one of the ideal catalytic concepts for improving an important
synthetic method.[18] Further studies to improve on this
catalytic reaction are currently in progress.
Entry
Conditions
Yield [%][a]
e.r.
1
2
3
4
5
6
7
standard conditions
Fe(Pc)!FeCl(TPP)
Fe(Pc)!Co(Pc)
Fe(Pc)!Cu(Pc)
Fe(Pc)!Mn(Pc)
Fe(Pc) 10 mol%!5 mol%
THF!CPME
79
20
4
2
98:2
92:8
–
–
2
–
63 (49)[b]
53 (80)[c]
60
99:1 (98:2)[b]
89:11 (97:3)[c]
8[d]
9
10
11
12[f]
at room temperature
under O2 atmosphere
without 8l
without 5ꢀ MS
scale up
98:2
98:2
1:99[e]
–
64
40
n.r.
84
95:5
[a] Yield of isolated product. [b] With 5 mol% of both Fe(Pc) and 8l.
[c] 908C, 12 h. [d] 48 h. [e] 1:99 or greater. [f] 60 h, 5 (10 mmol) was used.
CPME=cyclopentyl methyl ether, n.r.=no reaction, TPP=tetraphenyl-
porphyrin.
though the reaction was somewhat sluggish (entry 8). The use
of pure oxygen gas instead of air did not improve the result
(entry 9). Reaction in the absence of catalyst 8l gave no
inversion product 7, but rather gave the corresponding
retention product (entry 10).[13] As described above
(Scheme 2), 5ꢀ MS seem to be essential in this reaction
(entry 11). Although an exact explanation for this effect is
difficult, 5ꢀ MS might remove water or hydroperoxide
generated by oxidation of the hydrazine catalyst with oxygen.
A scaled-up reaction (10 mmol of 5) was somewhat slow, but
gave inversion product 7 in almost the same yield, but slightly
lower enantiomeric ratio, than that of the small-scale reaction
(entry 12).
With the optimized conditions in hand, we investigated
the reactions of several alcohols and nucleophiles (Table 3).
In addition to carboxylic acids, such as benzoic acid and
4-nitrobenzoic acid, phenol, N-hydroxyphthalimide, phthali-
mide, and N-benzyl-2-nitrobenzenesulfonylamide[15] reacted
with 3-phenylpropanol (10) under the catalytic Mitsunobu
conditions to provide the corresponding substituted products
11–16 (Table 3, entries 1–6).[2] As with reactions of (ꢀ)-(S)-
ethyl lactate (5) with carboxylic acids to give inversion
products 7 and 17 (entries 7 and 8), other secondary alcohols
such as (+)-(R)-3-butyn-2-ol (18), (+)-(R)-1-phenyl-1-etha-
nol (20), (+)-(S)-2-octanol (22), (ꢁ)-(1R*,5R*)-3,3,5-trime-
thylcyclohexa-1-ol (24), and dihydrocholesterol (26) under-
went inversion of stereochemistry to give the corresponding
esters 19, 21, 23, 25, and 27, respectively, with high enantio-
meric or diastereomeric purities (entries 9–13). On the other
hand, when sterically hindered (ꢀ)-menthol (28) was used as
a substrate, the yield and ratio of inversion product 29 were
low (entry 14).[13] Although sensitivity to steric factors is one
of the problems with the original Mitsunobu reaction, the use
of highly acidic carboxylic acids such as 4-nitrobenzoic acid
Experimental Section
Typical procedure for catalytic Mitsunobu reactions: A mixture of
(ꢀ)-(S)-ethyl lactate (5; 100 mg, 0.850 mmol), 3,5-dinitrobenzoic acid
(6; 198 mg, 0.935 mmol), triphenylphosphine (446 mg, 1.70 mmol),
hydrazine 8l (21.2 mg, 0.0850 mmol), iron phthalocyanine (48.3 mg,
0.0850 mmol) and activated 5ꢀ MS (400 mg) in THF (1.7 mL) was
heated at 658C under air (balloon). After the reaction mixture was
cooled to room temperature and filtered, the solvent was removed
under reduced pressure. The residue was purified by silica gel
chromatography (n-hexane/EtOAc, 6:1). Ethyl 2-(3,4-dichlorophe-
nyl)azocarboxylate (20.1 mg, 0.0813 mmol, 96%) was recovered from
the first fraction as a red solid (see the Supporting Information for
spectroscopic data). The second fraction gave (R)-7[5b] (209 mg,
1
0.668 mmol, 79%, 98:2 e.r.) as a white solid; mp 98–998C; H NMR
(600 MHz, CDCl3): d = 9.254–9.247 (m, 1H), 9.20 (d, J = 2.1 Hz, 2H),
5.42 (q, J = 6.9 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.73 (d, J = 6.9 Hz,
3H), 1.32 ppm (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): d =
169.6, 161.9, 148.7, 133.2, 129.6, 122.6, 70.8, 61.9, 16.9, 14.1 ppm. The
enantiomeric ratio was determined by HPLC analysis with a chiral
stationary phase. Chiral HPLC: Daicel-Chiralpak OJ-H 46 ꢁ 150 mm,
254 nm UV detector, room temperature eluent: (n-hexane/iPrOH)
1:5, flow rate: 0.5 mLminꢀ1, retention time (min) 17.0 (S isomer), 20.2
22
(R isomer). ½aꢂD ¼ꢀ8.1 (c = 1.00, CHCl3) [(S)-1-ethoxycarbonylethyl
22
3,5-dinitrobenzoate (> 99:1 er): ½aꢂD ¼ + 8.8 (c = 1.00, CHCl3)].
Received: January 8, 2013
Published online: && &&, &&&&
Keywords: alcohols · iron catalysis · Mitsunobu reaction ·
.
oxygen · synthetic methods
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Table 3: Catalytic Mitsunobu reaction scope.[a]
Entry Alcohol Product
Yield [%][b]
(selectivity)
Entry
8
Alcohol
Product
Yield [%][b]
(selectivity)
5
79
1
71
92
55
64
(>99:1 e.r.)
(98:2 e.r.)
91
2
3
4
10
10
10
9
(97:3 e.r.)
73
10
11
(93:7 e.r.)
70
(94:6 e.r.)
57
5
6
10
10
65
51
12
13
(92:8 d.r.)
67
(97:3 d.r.)
50
28
7
14
(97:3 e.r.)
(25:75 d.r.)
[a] Reaction conditions: Alcohol (0.734–0.850 mmol), nucleophile (1.1 equiv), 8l (10 mol%), Fe(Pc) (10 mol%), PPh3 (2 equiv), 5ꢀ MS (345–400 mg)
in THF (0.50m) at 658C under air for 12–48 h. [b] Yield of isolated product. Bn=benzyl, Ns=2-nitrobenzenesulfonyl.
[6] The possibility of conducting a Mitsunobu reaction using
[1] a) O. Mitsunobu, M. Yamada, T. Mukaiyama, Bull. Chem. Soc.
Jpn. 1967, 40, 935 – 939; b) O. Mitsunobu, M. T. Yamada, Bull.
Chem. Soc. Jpn. 1967, 40, 2380 – 2382.
[2] For reviews, see: a) O. Mitsunobu, Synlett 1981, 1 – 28; b) D. L.
Hughes, Org. React. 1992, 42, 335 – 656; c) T. Y. S. But, P. H. Toy,
Chem. Asian J. 2007, 2, 1340 – 1355; d) K. C. Kumara Swamy,
N. N. Bhuvan Kumar, E. Balaraman, K. V. P. Pavan Kumar,
Chem. Rev. 2009, 109, 2551 – 2651.
[3] For reviews on the modification of Mitsunobu reactions, see:
a) R. Dembinski, Eur. J. Org. Chem. 2004, 2763 – 2772; b) S.
Dandapani, D. P. Curran, Chem. Eur. J. 2004, 10, 3130 – 3138; see
also Refs [2c] and [2d]. For a recent example of modification,
see: c) M. Figlus, N. Wellaway, A. W. J. Cooper, S. L. Sollis, R. C.
Hartley, ACS Comb. Sci. 2011, 13, 280 – 285.
[4] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L.
Leazer, Jr., R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearl-
man, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411 –
420.
a catalytic amount of a phosphine reagent has been reported
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2010. For related reports, see: b) C. J. OꢂBrien, J. L. Tellez, Z. S.
Nixon, L. J. Kang, A. L. Carter, S. R. Kunkel, K. C. Przeworski,
G. A. Chass, Angew. Chem. 2009, 121, 6968 – 6971; Angew.
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Chem. 2010, 122, 10352 – 10355; Angew. Chem. Int. Ed. 2010, 49,
10154 – 10157.
[8] The preparation of N,N,N’,N’-tetramethylazodicarboxamide
(TMAD) by palladium-catalyzed aerobic oxidation of the
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Tsunoda, K. Nishii, Japan Patent Kokai P2008 – 214301A, 2008.
[9] For examples of aerobic oxidation of hydrazine compounds, see:
a) S. G. Cohen, R. Zand, C. Steel, J. Am. Chem. Soc. 1961, 83,
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[10] G. Gaviraghi, M. Pinza, G. Pifferi, Synthesis 1981, 608 – 610.
[11] Y. Zhao, F. G. Bordwell, J.-P. Cheng, D. Wang, J. Am. Chem. Soc.
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hardly formed under air, see: K. Watanabe, N. Yamagiwa, Y.
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[15] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36,
6373 – 6374.
[12] For reviews on catalytic reactions using molecular oxygen, see:
a) S. S. Stahl, Angew. Chem. 2004, 116, 3480 – 3501; Angew.
Chem. Int. Ed. 2004, 43, 3400 – 3420; b) T. Punniyamurthy, S.
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[13] We have reported condensation reactions between alcohols and
carboxylic acids using triphenylphosphine and atmospheric
oxygen in the presence of a catalytic amount of Fe(Pc). The
stereochemistry of esters obtained from chiral secondary
alcohols was absolutely retained in this reaction, see: T.
Taniguchi, D. Hirose, H. Ishibashi, ACS Catal. 2011, 1, 1469 –
1474. This esterification could compete with the present catalytic
Mitsunobu reaction and decrease inversion products in some
cases.
[16] S. F. Martin, J. A. Dodge, Tetrahedron Lett. 1991, 32, 3017 – 3020.
[17] For recent examples of Fe(Pc)-catalyzed reactions, see: a) A. A.
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D. G. Knorre, O. S. Fedorova, Bioorg. Med. Chem. Lett. 2009, 19,
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Nemykin, Adv. Synth. Catal. 2009, 351, 3168 – 3174; c) T.
Taniguchi, N. Goto, A. Nishibata, H. Ishibashi, Org. Lett. 2010,
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[18] Markꢄ and co-workers have reported the copper-catalyzed
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5882, and references therein.
[14] Although we never detected peroxides from THF in the present
reaction, attention should be given to the possibility of an
explosion when a combination of THF and air is used. CPME is
a good substitute for THF because the corresponding peroxide is
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Communications
Synthetic Methods
D. Hirose, T. Taniguchi,*
H. Ishibashi
&&&& — &&&&
Recyclable Mitsunobu Reagents:
Catalytic Mitsunobu Reactions with an
Iron Catalyst and Atmospheric Oxygen
Aerobic recycling: A catalytic amount of
a hydrazine reagent is sufficient to pro-
mote Mitsunobu reactions in the pres-
ence of triphenylphosphine, an iron cat-
alyst, and air. The active form of the
catalyst, an azo species, can be readily
generated by iron-catalyzed aerobic oxi-
dation. MS=molecular sieves, Pc=
phthalocyanine.
6
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