N-isopropylidene-N′-2-nitrobenzenesulfonyl hydrazine, a reagent for reduction of alcohols via the corresponding monoalkyl diazenes

Article abstract of DOI:10.1021/jo062325p

The reagent N-isopropylidene-N′-2-nitrobenzenesulfonyl hydrazine (IPNBSH) is used in the reduction of alcohols via the loss of dinitrogen from transiently formed monoalkyl diazene intermediates accessed by sequential Mitsunobu displacement, hydrolysis, and fragmentation under mild reaction conditions.

Full text of DOI:10.1021/jo062325p

SCHEME 1
N-Isopropylidene-N′-2-nitrobenzenesulfonyl
Hydrazine, a Reagent for Reduction of Alcohols
via the Corresponding Monoalkyl Diazenes
Mohammad Movassaghi* and Omar K. Ahmad
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
moVassag@mit.edu
ReceiVed NoVember 11, 2006
NBSH in the reduction of allylic, benzylic, and saturated
alcohols.3b,c This direct reduction of alcohols via the corre-
sponding monoalkyl diazene intermediates under mild reaction
conditions presents a highly versatile methodology for organic
synthesis.6 We recently reported the use of the related reagent
N-isopropylidene-N′-2-nitrobenzenesulfonyl hydrazine (IPN-
BSH) for a difficult allylic reductive transposition step in our
total syntheses of (-)-acylfulvene and (-)-irofulven.7 Herein
we report our results on the general utility of IPNBSH, a reagent
complimentary to NBSH, for conversion of alcohols to the
corresponding monoalkyl diazene intermediates.
The reagent N-isopropylidene-N′-2-nitrobenzenesulfonyl hy-
drazine (IPNBSH) is used in the reduction of alcohols via
the loss of dinitrogen from transiently formed monoalkyl
diazene intermediates accessed by sequential Mitsunobu
displacement, hydrolysis, and fragmentation under mild
reaction conditions.
The stereospecific displacement of an alcohol by the reagent
NBSH under the Mitsunobu reaction conditions affords the
corresponding 1,1-disubstituted sulfonyl hydrazine 2 (Scheme
1).3 Warming of the reaction mixture to ambient temperature
provides the corresponding monoalkyl diazene 3 by elimination
of 2-nitrobenzenesulfinic acid. Sigmatropic3a,b loss of dinitrogen
from the unsaturated monoalkyl diazene or expulsion of
dinitrogen via a free-radical3c pathway from the saturated
monoalkyl diazene affords the corresponding reduction product.
The thermal sensitivity of NBSH in solution and the corre-
sponding Mitsunobu adduct 2 necessitate the execution of the
initial step in these transformations at subambient temperatures
(-30 to -15 °C). Lower reaction temperatures obviate a
competitive and undesired Mitsunobu reaction of the alcohol
substrate with 2-nitrobenzenesulfinic acid, the thermal decom-
position8 product of NBSH or adduct 2.3 For less reactive
alcohols, the use of higher substrate concentrations and excess
reagents in N-methyl morpholine has been described.3b,c
The loss of dinitrogen from monoalkyl diazene intermediates
is common in a wide range of transformations in organic
chemistry.1,2 Several powerful methodologies for carbonyl
reduction involve initial condensation with an arenesulfonyl
hydrazine followed by reduction of the corresponding hydrazone
leading to the loss of dinitrogen. In 1996, Myers reported a
highly efficient, mild, and stereospecific conversion of a variety
of propargylic alcohols to the corresponding allenes3a via a
Mitsunobu4 reaction using the reagent 2-nitrobenzenesulfonyl
hydrazide5 (NBSH). Subsequent reports discussed the use of
(1) For representative examples, see: (a) Szmant, H. H.; Harnsberger,
H. F.; Butler, T. J.; Barie, W. P. J. Org. Chem. 1952, 74, 2724. (b) Nickon,
A.; Hill, A. S. J. Am. Chem. Soc. 1964, 86, 1152. (c) Corey, E. J.; Cane,
D. E.; Libit, L. J. Am. Chem. Soc. 1971, 93, 7016. (d) Hutchins, R. O.;
Kacher, M.; Rua, L. J. Org. Chem. 1975, 40, 923. (e) Kabalka, G. W.;
Chandler, J. H. Synth. Commun. 1979, 9, 275. (f) Corey, E. J.; Wess, G.;
Xiang, Y. B.; Singh, A. K. J. Am. Chem. Soc. 1987, 109, 4717. (g) Myers,
A. G.; Kukkola, P. J. J. Am. Chem. Soc. 1990, 112, 8208. (h) Myers, A.
G.; Finney, N. S. J. Am. Chem. Soc. 1990, 112, 9641. (i) Guziec, F. S., Jr.;
Wei, D. J. Org. Chem. 1992, 57, 3772. (j) Wood, J. L.; Porco, J. A., Jr.;
Taunton, J.; Lee, A. Y.; Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc.
1992, 114, 5898. (k) Bregant, T. M.; Groppe, J.; Little, R. D. J. Am. Chem.
Soc. 1994, 116, 3635. (l) Ott, G. R.; Heathcock, C. H. Org. Lett. 1999, 1,
1475. (m) Chai, Y.; Vicic, D. A.; McIntosh, M. C. Org. Lett. 2003, 5, 1039.
(n) Sammis, G. M.; Flamme, E. M.; Xie, H.; Ho, D. M.; Sorensen, E. J. J.
Am. Chem. Soc. 2005, 127, 8612.
(2) (a) Kosower, E. M. Acc. Chem. Res. 1971, 4, 193. (b) Tsuji, T.;
Kosower, E. M. J. Am. Chem. Soc. 1971, 93, 1992.
(3) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (b)
Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841. (c) Myers, A.
G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572.
(4) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React.
1982, 42, 335.
We recently found the use of the reagent IPNBSH to be
advantageous over NBSH in a surprisingly difficult9 reductive
(6) For examples in the utility of NBSH in synthesis, see: (a) Shepard,
M. S.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 2597. (b) Corey, E. J.;
Huang, A. X. J. Am. Chem. Soc. 1999, 121, 710. (c) Arredondo, V. M.;
Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633.
(d) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121, 9562. (e)
Charette, A. B.; Jolicoeur, E.; Bydlinski, G. A. S. Org. Lett. 2001, 3, 3293.
(f) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771. (g) Rega´s,
D.; Afonso, M. M.; Rodr´ıguez, M. L.; Palenzuela, J. A. J. Org. Chem.
2003, 68, 7845. (h) McGrath, M. J.; Fletcher, M. T.; Ko¨nig, W. A.; Moore,
C. J.; Cribb, B. W.; Allsopp, P. G.; Kitching, W. J. Org. Chem. 2003, 68,
3739. (i) Ng, S.-S., Jamison, T. F. Tetrahedron 2005, 61, 11405. (j) Michael,
F. E.; Duncan, A. P.; Sweeney, Z. K.; Bergman, R. G. J. Am. Chem. Soc.
2005, 127, 1752. (k) Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel,
D. R.; Myers, A. G. Science 2005, 308, 395.
(5) (a) Dann, A. T.; Davies, W. J. Chem. Soc. 1929, 1050. (b) Myers,
A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507. (c) Myers,
A. G.; Movassaghi M. In e-Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed; John Wiley & Sons: New York, 2003.
(7) Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem.,
Int. Ed. 2006, 45, 5859.
(8) Hu¨nig, S.; Mu¨ller, H. R.; Thier, W. Angew. Chem., Int. Ed. Engl.
1965, 4, 271.
10.1021/jo062325p CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/03/2007
1838
J. Org. Chem. 2007, 72, 1838-1841

TABLE 1. Reduction of Alcohols Using IPNBSHa
SCHEME 2
solid. Comparison of the X-ray structure of IPNBSH10 with that
of the closely related acetone p-toluenesulfonyl hydrazone11
reveals longer C-S (1.774 vs 1.753 Å) and slightly shorter
N(2)-S (1.636 vs 1.637 Å) bonds consistent with greater
interaction between the nitrogen(2) and sulfur in IPNBSH. The
smaller N-N-S bond angle found in IPNBSH (112.4° vs
114.1°) was expected to reduce the steric interaction of the syn-
coplanar N-H and C-Me groups.
Significantly, the greater thermal stability of IPNBSH com-
pared to that of NBSH was expected to provide flexibility for
the Mitsunobu reaction while offering equally rapid thermal
fragmentation after hydrolysis of the adduct 4 (Scheme 1). For
comparison, heating a solution of IPNBSH in DMSO-d6 (0.02
M) at 50 °C for 30 min did not result in decomposition, whereas
a significant quantity of NBSH (∼60%) was found to fragment
under the same conditions. Solutions of IPNBSH as described
above did not decompose at 75 or 100 °C after 30 min, whereas
considerable decomposition was observed at 150 °C within
minutes. The greater thermal stability of IPNBSH allows it to
be stored at room temperature for several months.5b,c,12
The utility of IPNBSH in the challenging7 reductive allylic
transposition mentioned above prompted our evaluation of this
reagent’s broader utility for organic synthesis. Addition of
diethylazodicarboxylate (DEAD, 1.20 equiv) to a solution of
trans,trans-farnesol (1a, 1 equiv, Scheme 2), IPNBSH (1.21
equiv), and triphenylphosphine (Ph3P, 1.21 equiv) in THF (9.0
mL) rapidly (15 min) provided the desired Mitsunobu adduct
4a in 86% isolated yield. The isolation of 4a is not necessary,
and its direct hydrolysis under optimal conditions was achieved
by introduction of trifluoroethanol-water (1:1) upon completion
of the Mitsunobu reaction.13 The hydrolysis step results in
a Conditions: Ph3P (1.2 equiv), DEAD (1.2 equiv), IPNBSH (1.2 equiv),
THF (0.1 M), 0 f 23 °C, 2 h; TFE-H2O (1:1), 2 h. b Average of two
experiments. c Reference 7. d Hydrolysis step required 3 h. e Mitsunobu
reaction was complete in 15 min. f E:Z ) 93:7. g 2.0 equiv of reagents was
used; contains <8% of C5-diastereomer. h 1.6 and 2.5 equiv of reagents
was used in entries 8 and 9, respectively; PhNHNH2 (5.0 equiv) was used
in place of TFE-H2O.
allylic transposition reaction.7 In reduction of the substrate in
entry 1 of Table 1, IPNBSH provided greater flexibility with
respect to solvent choice, reaction temperature, order of addition,
and concentration of substrate and reagents. As shown in
Scheme 1, the Mitsunobu displacement of an alcohol with
IPNBSH results in the stable and isolable arenesulfonyl hydra-
zone 4. We developed mild reaction conditions for in situ
hydrolysis of hydrazone 4 to the same hydrazine 2 accessed
using NBSH (Scheme 1).
(9) For other examples, see: (a) Ott, G. R.; Heathcock, C. H. Org. Lett.
1999, 1, 1475. (b) The use of high reaction temperatures described in
Vostrikov, N. S.; Vasikov, V. Z.; Miftakhov, M. S. Russ. J. Org. Chem.
2005, 41, 967 likely cause decomposition of NBSH.
(10) See Supporting Information for the crystal structure of IPNBSH.
(11) Ojala, C. R.; Ojala, W. H.; Pennamon, S. Y.; Gleason, W. B. Acta
Crystallogr. 1998, C54, 57.
(12) Due to potential toxicity and flammability of IPNBSH similar to
that of related arenesulfonylhydrazides (e.g., p-toluenesulfonylhydrazide),
prudent experimental practices should be followed in handling of IPNBSH
with gloves under inert atmosphere. See Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed; John Wiley & Sons: New York,
1995; Vol. 7, p 4953.
IPNBSH can be prepared by dissolution of the readily
available NBSH5 in acetone (eq 1). For optimal results, IPNBSH
is triturated with hexanes to give the desired reagent as a white
J. Org. Chem, Vol. 72, No. 5, 2007 1839

SCHEME 3
fragmentation of 2-nitrobenzenesulfinic acid followed by sig-
matropic loss of dinitrogen to give the triene 5a in 87% isolated
yield. The ease of hydrolysis of these hydrazones under mild
conditions is likely due to the rapid fragmentation of the
corresponding sulfonyl hydrazine derivatives at room temper-
ature.14
A uniform set of reaction conditions proved effective for a
single-step reduction of a range of alcohols (Table 1). Allylic
alcohols (Table 1, entries 1-5) and propargylic alcohols (Table
1, entries 6 and 7) provided the desired reduction products via
the expected sigmatropic loss of dinitrogen from the intermediate
monoalkyl diazenes generated by in situ hydrolysis. For
unhindered primary alcohols the reaction could be conducted
at even lower concentration (0.05 M) and subambient temper-
atures with equal efficiency. The use of IPNBSH allowed the
use of other solvents (e.g., toluene, fluorobenzene, and chlo-
robenzene) in place of THF with similar results.
single-step N-alkylation-reduction strategy offers a valuable
alternative to the approach based on the Mitsunobu reaction.9a
Interestingly, while the Mitsunobu reaction with the primary
alcohol in entry 8 of Table 1 proceeded smoothly under standard
conditions (adduct isolated in 93% yield), the hydrolysis of the
corresponding hydrazone adduct 4 under the conditions used
for propargylic and allylic substrates proved ineffective, afford-
ing less than 20% yield of the desired reduction product.15
We reasoned that although slow hydrolysis and generation
of unsaturated (propargylic and allylic) monoalkyl diazenes led
to an efficient sigmatropic loss of dinitrogen, the loss of
dinitrogen from saturated monoalkyl diazenes would be optimal
at higher concentrations of the diazene intermediate.16 The
replacement of the hydrolysis step with a hydrazone exchange
reaction (phenylhydrazine) reduced the time for the complete
consumption of the Mitsunobu adduct from 4 h to 30 min (TLC
analysis).17 A limitation of IPNBSH is its greater sensitivity
toward sterically hindered substrates as compared to NBSH.
For example, the Mitsunobu reaction with the saturated second-
ary alcohol in entry 9 of Table 1 proved difficult as compared
to the reaction of unsaturated secondary alcohols (Table 1,
entries 4-7).18 The use of more forcing reaction conditions with
the alcohol in entry 9 of Table 1 did not increase the isolated
yield of the desired product and returned the starting alcohol.19
The thermal stability of IPNBSH allows for unique transfor-
mations such as the one shown in eq 2. N-Alkylation of the
corresponding sodium sulfonamide of IPNBSH with allylic
bromide 6 followed by in situ hydrolysis afforded the desired
terminal alkene 5a via sigmatropic loss of dinitrogen. This
In addition to IPNBSH, we examined a series of other
hydrazone derivatives as potential reagents for the conversion
of alcohols to the corresponding monoalkyl diazenes. These
included the 2-nitrobenzenesulfonyl hydrazones of trifluoroac-
etone, dichloroacetone, cyclobutanone, benzaldehyde, acetal-
dehyde, and trimethylacetaldehyde, in addition to methane-
sulfonyl hydrazones of acetone and benzaldehyde. IPNBSH was
identified as the best reagent on the basis of optimal reactivity
in the Mitsunobu reaction and ease of hydrolysis of the
corresponding adduct. Interestingly, although the Mitsunobu
reaction of the aldehyde hydrazone derivatives proceeded with
efficiency equal to that of IPNBSH, their hydrolysis gave the
corresponding carbonyl hydrazide and not the expected reduction
product (Scheme 3). This is likely due to isomerization20 of
transient R-hydroxyalkyldiazene intermediates 10a-b.
In conclusion, the reagent IPNBSH serves as a reagent
complementary to NBSH for conversion of alcohols to the
corresponding reduction products via monoalkyl diazene inter-
mediates. Attractive features of this reagent include ease of
preparation, storage, and use due to excellent thermal stability.
IPNBSH offers flexibility with respect to choice of reaction
solvent, reaction temperature, order of addition, and concentra-
tion of substrate and reagents in the Mitsunobu reaction. We
expect IPNBSH will find applications in unique transformations
such as that illustrated in eq 2.
(13) These conditions for the hydrolysis step were found to be superior
to others explored, including the use of substoichiometric quantities of acetic
acid or Sc(OTf)3 or the use of other co-solvents (MeOH and EtOH).
(14) Consistent with this hypothesis, hydrolysis of the Mitsunobu adducts
of secondary alcohols is faster than with those derived from primary
alcohols.
(15) Addition of acetic acid, 2,6-lutidine, or 1,4-cyclohexadiene and the
use of ethanedithiol instead of water did not improve the yield of the
reduction product.
(16) A faster release of the sulfonyl hydrazine derivative 2 and formation
of the diazene intermediate 3 could provide a more efficient free-radical
loss of dinitrogen. Please see ref 2 and Myers, A. G.; Movassaghi, M.;
Zheng, B. Tetrahedron Lett. 1997, 38, 6569.
Experimental Section
(E)-3,7,11-Trimethyldodeca-1,6,10-triene (5a, Table 1, entry
3). DEAD (74 µL, 0.47 mmol, 1.2 equiv) was added dropwise to
a solution of IPNBSH (122 mg, 0.474 mmol, 1.21 equiv),
trans,trans-farnesol (1a, 0.100 mL, 0.393 mmol, 1 equiv), and
triphenylphosphine (124 mg, 0.473 mmol, 1.21 equiv) in anhydrous
THF (9.0 mL) at 0 °C under an argon atmosphere. After 5 min,
the reaction mixture was allowed to warm to 23 °C. After 20 min,
a mixture of trifluoroethanol and water (1:1, 4.5 mL) was added to
the reaction mixture to enable formation of the allylic diazene
(17) The addition of phenylhydrazine was only necessary in the deoxy-
genation of saturated alcohols.
(18) For comparison, the use of NBSH in the reduction of the saturated
secondary alcohol in entry 9 of Table 1 under optimum reaction conditions
provided the desired deoxygenated product in 80% yield. See ref 3c.
(19) Unfortunately, various procedural changes described in a more recent
and related report (Keith, J. M.; Gomez, L. J. Org. Chem. 2006, 71, 7113)
did not provide any advantage over our original reaction conditions in ref
7 for the use of IPNBSH in the Mitsunobu reaction.
(20) Tezuka, T.; Otsuka, T.; Wang, P.-C.; Murata, M. Tetrahedron Lett.
1986, 27, 3627.
1840 J. Org. Chem., Vol. 72, No. 5, 2007

intermediate. After 3 h, the reaction mixture was partitioned between
diethyl ether (25 mL) and water (25 mL), and the aqueous layer
was extracted with diethyl ether (2 × 25 mL). The combined
organic layers were dried over anhydrous sodium sulfate, filtered,
and concentrated. The residue was purified by flash column
water (25 mL). The organic layer was washed with water (2 × 25
mL), dried over anhydrous sodium sulfate, filtered, and concen-
trated. The residue was purified by flash column chromatography
on silica gel (100% npentane) to give the allene (36 mg, 70%). All
spectroscopic data were in agreement with the literature.22 1H NMR
(400 MHz, CDCl3, 20 °C): δ 7.31-7.28 (m, 2H), 7.22-7.21 (m,
3H), 5.17 (tt, 1H, J ) 13.2, 6.8 Hz), 4.69 (dt, 2H, J ) 6.8, 3.2
Hz), 2.75 (t, 2H, J ) 7.6 Hz), 2.35-2.32 (m, 2H). 13C NMR (500
MHz, CDCl3, 20 °C): δ 208.8, 142.0, 128.7, 128.5, 126.1, 89.6,
75.3, 35.6, 30.2. MS (m/z) C11H12 [M]+: 144. FTIR (thin film):
3027 (s), 2922 (s), 2855 (s), 1955 (s), 1495 (m), 1453 (m).
n
chromatography on silica gel (100% pentane) to give triene 5a
(71 mg, 87%). All spectroscopic data were in agreement with
literature.21 TLC (40% ethyl acetate in hexanes) Rf: 0.8 (CAM,
1
KMnO4). H NMR (400 MHz, CDCl3, 20 °C): δ 5.25-5.15 (m,
1H), 5.13-5.10 (m, 2H), 4.99 (t, 1H, J ) 2.0 Hz), 4.94-4.91 (m,
2H), 2.14-1.98 (m, 7H), 1.69 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H),
1.36-1.33 (m, 2H), 0.99 (d, 3H, J ) 8 Hz). 13C NMR (500 MHz,
CDCl3, 20 °C): δ 145.0, 135.1, 131.5, 124.7, 124.6, 112.7, 39.9,
37.5, 36.9, 26.9, 25.9, 25.8, 20.4, 20.4, 17.9, 16.2. MS (m/z) C15H26
[M]+: 206. FTIR (thin film): 3077 (m), 2966 (s), 2915 (s), 2856
(s), 1640 (m), 1453 (s), 1376 (s).
Acknowledgment. M.M. is a Dale F. and Betty Ann Frey
Damon Runyon Scholar supported by the Damon Runyon
Cancer Research Foundation (DRS-39-04). We thank Mr.
Michael A. Schmidt and Dr. Peter Mueller for X-ray crystal-
lographic analysis of IPNBSH. We acknowledge financial
support by NIH-NIGMS (GM074825), Paul M. Cook Fund,
Firmenich, Sigma-Aldrich, Amgen, and Boehringer Ingelheim
Pharmaceutical Inc.
5-Phenylpenta-1,2-diene (Table 1, Entry 6). DEAD (67.5 µL,
0.429 mmol, 1.20 equiv) was added dropwise to a solution of
IPNBSH (110 mg, 0.429 mmol, 1.20 equiv), 5-phenylpent-1-yn-
3-ol (57 mg, 0.36 mmol, 1 equiv), and triphenylphosphine (112
mg, 0.428 mmol, 1.20 equiv) in anhydrous THF (3.5 mL) at 0 °C
under an argon atmosphere. After 5 min, the reaction mixture was
allowed to warm to 23 °C. After 2 h, a mixture of trifluroethanol
and water (1:1, 1.7 mL) was added to the reaction mixture to enable
the formation of the propargylic diazene intermediate. After 2 h,
the reaction mixture was partitioned between npentane (25 mL) and
Supporting Information Available: Experimental procedures,
spectroscopic data for all new compounds, and the X-ray structure
of IPNBSH in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO062325P
(21) Saplay, K. M.; Sahni, R.; Damodaran, N. P.; Dev, S. Tetrahedron
1980, 36, 1455.
(22) Ohno, H.; Miyamura, K.; Tanaka, T. J. Org. Chem. 2002, 67, 1359.
J. Org. Chem, Vol. 72, No. 5, 2007 1841