Nonsymmetrical azocarbonamide carboxylates as effective Mitsunobu reagents

Article abstract of DOI:10.1002/ejoc.201403152

A family of nonsymmetrical Mitsunobu reagents possessing both dialkyl amide and ester substituents was developed. These new reagents were readily prepared in a single pot from inexpensive, commercially available materials by using a scalable and environmentally friendly procedure. They were shown to exhibit activity parallel to that of diethyl azodicarboxylate/diisopropyl azodicarboxylate in a wide variety of Mitsunobu reactions. Importantly, the acyl hydrazine reaction byproducts were readily separable from the crude mixture by standard aqueous workup. In addition, the discovery of effective nonsymmetrical Mitsunobu reagents offers new directions for the ongoing development of this important reaction.

Full text of DOI:10.1002/ejoc.201403152

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403152
Nonsymmetrical Azocarbonamide Carboxylates as Effective Mitsunobu
Reagents
Daniel P. Furkert,*[a] Benjamin Breitenbach,[a] Ludovic Juen,[a] Ina Sroka,[a]
Mathilde Pantin,[a] and Margaret A. Brimble*[a]
Keywords: Synthetic methods / Azo compounds / C–O bond formation / C–N bond formation
A family of nonsymmetrical Mitsunobu reagents possessing
both dialkyl amide and ester substituents was developed.
These new reagents were readily prepared in a single pot
from inexpensive, commercially available materials by using
a scalable and environmentally friendly procedure. They
were shown to exhibit activity parallel to that of diethyl azo-
dicarboxylate/diisopropyl azodicarboxylate in a wide variety
of Mitsunobu reactions. Importantly, the acyl hydrazine reac-
tion byproducts were readily separable from the crude mix-
ture by standard aqueous workup. In addition, the discovery
of effective nonsymmetrical Mitsunobu reagents offers new
directions for the ongoing development of this important re-
action.
reagents have also been reported; these reagents can be re-
oxidized to regenerate the active azo compound in situ.[8]
Introduction
The Mitsunobu reaction remains a mainstay in organic
synthesis owing to its wide substrate scope, stereospecificity,
and mild conditions.[1] It is a convenient and reliable pro-
cedure for many transformations including alcohol stereo-
inversion, esterification, and conversion of alcohols into
amines, thioesters, and other functional groups.[2] Diethyl
and diisopropyl azodicarboxylates (DEAD 1a, DIAD 1b;
Figure 1) are currently the most widely used reagents. Close
analogues (see compounds 1c–f) have also been reported[3–5]
to address well-known problems associated with separation
of the hydrazine and/or phosphine oxide byproducts. Sym-
metrical azodicarbonamides 2a–d[6,7] were developed to re-
duce purification problems and to expand the reaction
scope. Cyanophosphoranes 3a and 3b allow the use of pro-
nucleophiles having pKa values up to 23.[7] Preliminary in-
vestigations into the use of catalytic amounts of Mitsunobu
Results and Discussion
In the course of our synthetic work, we required dimethyl
azodicarboxylate (DMAD, 1e) for the synthesis of N-Boc-
serine lactone 4 (Boc = tert-butoxycarbonyl; Figure 2);
however, neither 1e nor the literature precursor were readily
available. The principle advantage of 1e in this particular
case is that the byproduct diacyl hydrazine is more readily
separated from 4 by chromatography owing to the fact that
its polarity is higher than that of the diacyl hydrazines
derived from 1a and 1b. We reasoned that replacement of
one of the esters in 1a–e with a polar dimethylamide group
should similarly confer high polarity upon the correspond-
ing diacyl hydrazine byproducts while retaining the same
reactivity. In addition, synthesis of proposed azocarbon-
amide carboxylate (ACC) Mitsunobu reagents 5a–c
appeared potentially more robust and amenable to scale up
than recent azodicarboxylate preparations [e.g., di-p-
chlorobenzyl azodicarboxylate (DCAD), 1d[4]] that are
based on carbonyl diimidazole functionalization and oxi-
dation over two steps. We were further encouraged to con-
duct our study by the fact that requisite carbazates 6a–c
and dimethyl carbamyl chloride (8) are stable, inexpensive,
and commercially available in bulk quantities.
Figure 1. Mitsunobu reagents.
Acylation of carbazates 6a–c (Scheme 1, top) with di-
methyl carbamyl chloride (8) proceeded smoothly by using
a range of solvents (THF, MeCN, EtOAc) and bases
(K2CO3, NaHCO3, pyridine, Et3N). A slightly elevated tem-
perature (50 °C) and/or concentration (0.3 m) were required
for full conversion into 7a–c within 16 h. More forcing con-
[a] School of Chemical Sciences, The University of Auckland,
23 Symonds St, Auckland, New Zealand
E-mail: d.furkert@auckland.ac.nz
http://brimble.chem.auckland.ac.nz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403152.
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D. P. Furkert, M. A. Brimble et al.
SHORT COMMUNICATION
bromosuccinimide (NBS), but prior filtration to remove in-
organic or protonated nitrogen salts present in the mixtures
of the crude hydrazine was necessary to achieve good con-
versions. Additionally, chromatographic separation of
succinimide was required in the latter case.
Subsequent screening of alternative oxidants revealed
that both NaBr and NaCl were effective catalysts for the
oxidation reaction in the presence of an excess amount
aqueous Oxone through the in situ production of bromine
or chlorine, respectively.[11] On the basis of this finding, it
appeared that if sodium hydroxide was used as the base in
the acylation step, the chloride salt byproduct present could
go on to function as the oxidation catalyst in the second
step. We were pleased to find that this approach worked
very efficiently in practice. The final optimized conditions
involved acylation of 6a–c (1.0 equiv.) with dimethyl carb-
amyl chloride (8, 1.0 equiv.) and powdered sodium hydrox-
ide (1.0 equiv.) in ethyl acetate (0.3 m) at 50 °C for 16 h.
Once the acylation step was judged to be complete by TLC
Figure 2. N-Boc serine lactone 4 and novel azocarbonamide carb-
oxylate (ACC) Mitsunobu reagents 5a–c prepared in this work.[9]
ditions, however, led to some formation of bis-acylated
hydrazine 9 (Figure 3).
1
and/or H NMR spectroscopy, the addition of water and
Oxone rapidly effected the desired oxidation to afford 5a–c
in excellent yield (80–95% over two steps).
To establish the reactivity of our novel ACC reagents,
a range of Mitsunobu reactions previously conducted with
DEAD or DIAD were investigated by using 5a–c (Table 1).
Initial experiments verified that p-nitrobenzoic acid, com-
monly used for alcohol inversion, was readily esterified with
both methyl lactate (Table 1, entry 1) and glycidol (Table 1,
entry 2a)[12] in excellent yields. Reaction yields were ob-
served to vary somewhat with solvent (Table 1, entries 2b
and 2c). Overall, toluene and THF were found to be the
most generally useful reaction solvents, depending on sub-
strate solubility. 1-Phenyltetrazole-5-thiol, used to prepare
sulfones for Julia–Kocienski olefination, underwent alkyl-
ation with propargyl alcohol in high yield (Table 1, en-
try 3a).[13] Tributylphosphine was found to be largely effec-
tive in place of triphenylphosphine, but in some cases it
gave lower yields (Table 1, entries 3b–f).[14] In our hands,
reagents 5a–c performed almost identically in Mitsunobu
reactions under our standard conditions (Table 1, en-
tries 2a, 2d, 2e, 3a, 3g, and 3h). In our hands, reagent 5c
(DMAB) was generally the most convenient of the three to
prepare and to use in practice.
Scheme 1. Preparation of azocarbonamide carboxylates 5a–c.
Top: Two-step procedure. Bottom: One-pot procedure by using the
NaCl byproduct generated as the in situ chloride source for oxi-
dation of 7a–c.
Extension of the reaction scope to phthalimide alkyl-
ation (Table 1, entries 4 and 5)[15,16] and esterification of p-
methylbenzoic acid (Table 1, entry 6)[17] afforded the ex-
pected products in yields close to those reported in the
literature. Preparation of serine lactone 4 was identified to
be problematic, and this was attributed to facile ring open-
Figure 3. Structure of bis-acylated byproduct 9.
We were pleased to observe that hydrazines 7a–c were ing of the product, even by weak nucleophiles, and trouble-
relatively polar, as we had expected (Rf Ͻ 0.1; EtOAc/ some separation from Mitsunobu reagent byproducts.
hexanes, 4:1), and they exhibited a significant degree of Widely varying yields have been reported.[18a–18c] As a re-
aqueous solubility.[10] During the two-step preparation, sult, we were pleased to find that the use of 5a enabled
however, these attributes resulted in low yields (50–60%) of successful isolation of desired lactone 4 in moderate yields
compounds 5a–c owing to losses during aqueous washing after chromatography on a 1 g scale (Table 1, entry 7). The
of organic phases containing 7a–c. Oxidation of hydrazines considerably more stable trityl (Tr)-protected serine lactone
7a–c to corresponding azocarbonamide carboxylates 5a–c (Table 1, entry 8) was isolated in nearly quantitative yield
was facile with the use of either bromine/pyridine or N- under similar conditions.[19]
2
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Azocarbonamide Carboxylates as Effective Mitsunobu Reagents
Table 1. Representative Mitsunobu reactions by using azocarbonamide carboxylates 5a–c.
[a] Alcohol (1 equiv.), nucleophile (1.1 equiv.), and phosphine (1.1 equiv.) were dissolved in the appropriate solvent at room temperature,
and this was followed by the dropwise addition of specified reagent 5a–c. [b] Literature yields are given in brackets. [c] –78 °C to r.t.
over 18 h. [d] Reference reaction with 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), Et3N,
CH2Cl2.
ines are stable solids, and this suggests that their
Conclusions
chromatography-free isolation and sustainable reuse is an
In conclusion, a new family of Mitsunobu reagents based attainable future goal. We anticipate that the convenience
on the azocarbonamide carboxylate (ACC) framework was and economy of their preparation combined with the simple
developed. To the best of our knowledge, these are the first purification of the Mitsunobu reaction mixtures will make
nonsymmetrical reagents employed to date for this purpose. them a practically useful addition to the synthetic toolkit.
These novel reagents are conveniently prepared in high Further development of nonsymmetrical Mitsunobu rea-
yields in a single pot from commercially available materials gents should offer new possibilities for future development
and exhibit reactivity that is identical to that of commonly of this important reaction. Additional studies of the
used DEAD and DIAD on a wide range of substrates. fundamental chemistry and practical application of non-
Importantly, the diacyl hydrazine byproducts formed symmetrical azocarbonamide carboxylate compounds are
during the Mitsunobu reaction are readily removed by ongoing in our laboratories and will be reported in due
aqueous workup. Additionally, these novel diacyl hydraz- course.
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D. P. Furkert, M. A. Brimble et al.
SHORT COMMUNICATION
[4]
[5]
B. H. Lipshutz, D. W. Chung, B. Rich, R. Corral, Org. Lett.
2006, 8, 5069–5072.
Experimental Section
One-Pot Procedure for Synthesis of Azocarbonamide Carboxylate
a) J. Yang, L. Dai, X. Wang, Y. Chen, Tetrahedron 2011, 67,
1456–1462; b) J. Yang, L. Dai, X. Wang, Y. Chen, Chin. Chem.
Lett. 2011, 22, 1047–1050; c) K. Hagiya, N. Muramoto, T. Mis-
aki, T. Sugimura, Tetrahedron 2009, 65, 6109–6114; d) N. Iran-
poor, H. Firouzabadi, D. Khalili, S. Motevalli, J. Org. Chem.
2008, 73, 4882–4887; e) K. Hagiya, N. Muramoto, T. Misaki,
T. Sugimura, Tetrahedron 2009, 65, 6109–6114.
a) 2a (TMAD): T. Tsunoda, K. Uemoto, C. Nagino, M. Kawa-
mura, H. Kaku, S. Ito, Tetrahedron Lett. 1999, 40, 7355–7358;
b) 2b (ADDP): T. Tsunoda, Y. Yamakawa, S. Ito, Tetrahedron
Lett. 1993, 34, 1639–1642; c) 2c (ADDM): M. E. Lanning, S.
Fletcher, Tetrahedron Lett. 2013, 54, 4624–4628.
a) S. Ito, T. Tsunoda, Pure Appl. Chem. 1999, 71, 1053–1057,
and references cited therein; b) F. Drouet, A. F. M. Noisier,
C. S. Harris, D. P. Furkert, M. A. Brimble, Eur. J. Org. Chem.
2014, 1195–1201.
a) D. Hirose, T. Taniguchi, H. Ishibashi, Angew. Chem. Int. Ed.
2013, 52, 4613–4617; Angew. Chem. 2013, 125, 4711–4715; b)
T. Y. S. But, P. H. Toy, J. Am. Chem. Soc. 2006, 128, 9636–
9637; c) T. Y. S. But, J. Lu, P. H. Toy, Synlett 2010, 7, 1115–
1117.
The abbreviations DMAM, DMAE, and DMAB correspond
to (dimethylamino)methyl, (dimethylamino)ethyl and (dimeth-
ylamino)benzylazocarbonamide carboxylates, respectively.
These properties were expected to greatly simplify removal of
7a–c from Mitsunobu reaction mixtures involving ACC rea-
gents 5a–c.
a) P. T. Lang, A. M. Harned, J. E. Wissinger, J. Chem. Educ.
2011, 88, 652–656; b) control experiments confirmed that no
reaction occurred in the absence of the halide salt.
(ACC) Reagents 5a–c: A solution of carbazate 6a–c (1 equiv.), di-
methylcarbamyl chloride
8 (1 equiv.) and powdered NaOH
(1 equiv.) in ethyl acetate (0.3 m) was stirred at 50 °C for 16 h open
to air with a reflux condenser attached. Once the reaction was
judged to be complete (TLC), the mixture was cooled to room tem-
perature. Water (20% v/v) and Oxone (2 equiv.) were then added,
and the mixture became yellow-orange. After stirring for 15–
20 min, the phases were separated, and the aqueous layer was ex-
tracted with ethyl acetate. The combined organic extract was
washed with saturated aqueous thiosulfate, water, and brine; dried
with anhydrous MgSO4; and concentrated in vacuo. Flash
chromatography (hexane/ethyl acetate, 3:1; then, ethyl acetate,
100%) readily afforded the desired azocarbonamide carboxylate
compounds as yellow-orange oils, yields: 83 (for 5a), 95 (for 5b),
and 80% (for 5c).
[6]
[7]
[8]
Representative Procedure for Mitsunobu Reactions by using 5a–c: A
solution of 5a (100 mg, 0.62 mmol, 1.2 equiv.) in THF (0.5 mL)
was added to a stirred solution of glycidol (37.6 mg, 0.56 mmol),
p-nitrobenzoic acid (93.5 mg, 0.56 mmol, 1.1 equiv.), and tri-
phenylphosphine (140 mg, 0.56 mmol, 1.1 equiv.) in THF (1.0 mL)
at room temperature. The mixture was stirred until complete by
TLC (2 h) and then diluted with ethyl acetate. The organic phase
was washed with water and brine to remove hydrazine byproduct
7a, and it was then dried with anhydrous magnesium sulfate and
concentrated in vacuo. An analytical sample of (oxiran-2-yl)methyl
4-nitrobenzoate for characterization was obtained by chromatog-
raphy (hexanes/ethyl acetate, 9:1) as a slightly yellow powder
(114 mg, 93%). Data was in agreement with that previously re-
ported.[13]
[9]
[10]
[11]
[12] D. Camp, I. D. Jenkins, Aust. J. Chem. 1992, 45, 47–55.
[13] F. Aragozzini, E. Maconi, D. Potenza, C. Scolastico, Synthesis
1989, 3, 225–227.
[14] M. L. Blauvelt, A. R. Howell, J. Org. Chem. 2008, 73, 517–521.
[15] K. Tsuboyama, K. Takeda, K. Torii, H. Ogura, Chem. Pharm.
Bull. 1990, 38, 2357–2363.
Supporting Information (see footnote on the first page of this arti-
cle): Preparation of reagents 5a–c, characterization data, experi-
mental procedures, and copies of the 1H NMR and 13C NMR spec-
tra.
[16] O. Mitsunobu, M. Wada, T. Sano, J. Am. Chem. Soc. 1972, 94,
679–680.
[17] V. P. Fitzjarrald, R. Pongdee, Tetrahedron Lett. 2007, 48, 3553–
3557.
[18] a) S. V. Pansare, L. D. Arnold, J. C. Vederas, Org. Synth., Coll.
Vol. 9, p. 24, 1998; vol. 70, p. 10, 1992; b) C. M. Taylor, S. T.
De Silva, J. Org. Chem. 2011, 76, 5703–5708; c) L. D. Arnold,
T. H. Kalantar, J. C. Vederas, J. Am. Chem. Soc. 1985, 107,
7105–7109.
[1] a) O. Mitsunobu, Synthesis 1981, 1, 1–28; b) L. Kurti, B. Czako
(Eds.), Strategic Applications of Named Reactions in Organic
Synthesis, Elsevier, Burlington, MA, 2005, p. 294–295.
[2] K. C. Kumara Swamy, N. N. Bhuvan Kumar, E. Balaraman,
K. V. P. Pavan Kumar, Chem. Rev. 2009, 109, 2551–2651.
[3] a) L. A. Carpino, P. H. Terry, P. J. Crowley, J. Org. Chem. 1961,
26, 4336–4340; b) L. A. Carpino, P. J. Crowley, Org. Synth.
Coll. Vol. 5, 1973, p. 160; L. A. Carpino, P. J. Crowley, Org.
Synth. Coll. Vol. 44, 1964, p. 18.
[19] M. L. Blauvelt, A. R. Howell, J. Org. Chem. 2008, 73, 517–521.
Received: August 31, 2014
Published Online: ᭿
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Azocarbonamide Carboxylates as Effective Mitsunobu Reagents
Mitsunobu Reagents
A series of nonsymmetrical Mitsunobu re-
agents that avoid byproduct separation
problems in this useful reaction are re-
ported. They are readily prepared by a one-
pot sequence from inexpensive, commer-
cially available materials and are shown to
possess activity that is parallel to that of
diethyl azodicarboxylate/diisopropyl azo-
dicarboxylate in a wide range of synthetic
transformations.
D. P. Furkert,* B. Breitenbach, L. Juen,
I. Sroka, M. Pantin,
M. A. Brimble* ................................. 1–5
Nonsymmetrical Azocarbonamide Carb-
oxylates as Effective Mitsunobu Reagents
Keywords: Synthetic methods / Azo com-
pounds / C–O bond formation / C–N bond
formation
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