The Late Show with Rob! Tonight’s
Special Guest: Hydrazine
Robert Matunas
December 8
th
, 2004
Last One of the Year!!
Schmidt, E. W.,
Hydrazine and Its Derivatives
, Wiley-Interscience, New York, 2
nd
edn., 2001
Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines,
Chem. Soc. Rev.,
2001
,
30
, 205-213
The Late Show with Rob! Tonight’s
Special Guest: Hydrazine
Robert Matunas
January 5
th
, 2005
Happy New Year!!!
Schmidt, E. W.,
Hydrazine and Its Derivatives
, Wiley-Interscience, New York, 2
nd
edn., 2001
Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines,
Chem. Soc. Rev.,
2001
,
30
, 205-213
The Late Show with Rob! Tonight’s
Special Guest: Hydrazine
Robert Matunas
January 12
th
, 2005
(Third Time’s the Charm!)
Schmidt, E. W.,
Hydrazine and Its Derivatives
, Wiley-Interscience, New York, 2
nd
edn., 2001
Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines,
Chem. Soc. Rev.,
2001
,
30
, 205-213
The Late Show with Rob! Tonight’s
Special Guest: Hydrazine
Robert Matunas
January 19
th
, 2005
(I’ve Forgotten Everything)
Schmidt, E. W.,
Hydrazine and Its Derivatives
, Wiley-Interscience, New York, 2
nd
edn., 2001
Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines,
Chem. Soc. Rev.,
2001
,
30
, 205-213
Overview
•
Historical development of hydrazine (and friends)
•
Industrial outlook on hydrazine compounds
•
Selected synthetic methods for preparing simple
alkyl hydrazines
•
Some Myers Hydrazine Chemistry
It All Started with H. Emil Fischer (1852-1919)…
NH
2
N
N
HNO
2
Sulfite salts
H
N
NH
2
Phenylhydrazine!
Phenylhydrazine was the first hydrazine compound
discovered; Fischer synthesized it serendipitously in
1875 by reduction of the corresponding diazonium salt.
Fischer, E.
Ber. Dtsch. Chem. Ges.,
1875
,
8
, 589.
Some “Sweet” Synthesis
Fischer had been working on sugar syntheses, but lacked methods for obtaining the pure
compounds. Imagine making a sugar from scratch and then failing to isolate it!
Phenylhydrazine to the rescue!
CHO
CHOH
(CHOH)
3
CH
2
OH
Sugar
PhNHNH
2
HC
CHOH
(CHOH)
3
CH
2
OH
NNHPh
HC
C
(CHOH)
3
CH
2
OH
NNHPh
PhNHNH
2
O
PhNHNH
2
HC
C
(CHOH)
3
CH
2
OH
NNHPh
NNHPh
Osazone
AcOH
AcOH
AcOH
Fischer, E.
J. Am. Chem. Soc.,
1890
,
12
, 340-8.
Fischer, E.
Ber. Dtsch. Chem. Ges.,
1884
,
17
, 579.
Some Other Early Fischer Syntheses…
Fischer used some of the following strategies to prepare ~20 different
hydrazines, all before free hydrazine itself was known.
NH
R
1
R
2
nitrosation
N
R
1
R
2
NO
reduction
N
R
1
R
2
NH
2
N
H
N
H
O
R
R
nitrosation
N
N
H
O
R
R
NO
hydrolysis
reduction
N
N
H
O
R
R
NH
2
HN NH
2
R
HN NH
2
Ph
N NH
Ph
Bz
Bz
benzoylation
methylation
debenzoylation
N N
Ph
Bz
Bz
CH
3
N N
Ph
H
H
CH
3
The last preparation of a 1,2-disubstituted hydrazine anticipates the
modern dependence on protecting groups in synthesis.
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
…but Preparing Free Hydrazine Itself Took Time
Curtius eventually prepared free hydrazine (as the hydrate) via a circuitous route. The year was
1887, already 12 years after the discovery of phenylhydrazine. Since that time, about 20 other
hydrazine derivatives were already known!
EtO
O
H
N
N
2
KOH
HN
N N
NH
CO
2
K
KO
2
C
H
+
HN
N N
NH
CO
2
H
HO
2
C
H
+
H
2
N NH
2
2
+ 2
HO
O
OH
O
Hydrazine!
Curtius,
J. Prakt. Chem.
1889
,
39
, 107-39.
Molecular Properties of Hydrazine
Of the possible conformations for hydrazine, the gauche form is favored.
N
N
H
H
H
H
1.45
Å
1.02
Å
112
°
Bond Strengths:
N-N: ~ 50-60 kcal/mol
N-H: ~ 80-90 kcal/mol
Rotational Barrier:
6-10 kcal/mol
(vs. ~ 3 kcal/mol for ethane)
Hydrazine Production Today
Of the many methods available, the Raschig process is still in use (discovered 1907):
NH
3
+ NaOCl
ClNH
2
+ NaOH
ClNH
2
+ NH
3
+ NaOH
H
2
NNH
2
+ NaCl + H
2
O
Optimal ratio of reactants is
33:1 NH
3
:NaOCl!
The only waste produced is brine, but this is still a
significant issue on plant scale.
H
2
NNH
2
+ ClNH
2
2 NH
4
Cl + N
2
The major side reaction is destruction of the product
hydrazine by further reaction with chloramine.
An Improved Process for Hydrazine Production: The
Atofina-PCUK “Cycle”
R
1
R
2
O + NH
3
R
1
R
2
NH
- H
2
O
O
O
R
3
R
3
R
1
R
2
NH
O
+ R
3
OR
3
+ NH
3
- H
2
O
R
1
R
2
N
NH
2
R
1
R
2
O
R
1
R
2
N N
R
1
R
2
- H
2
O
+ 2 H
2
O
H
2
NNH
2
!
R
1
, R
2
= Me or Et; R
3
= H
Raschig Process: 4 tons NaCl/ton of hydrazine; 60% yield (based on NH
3
); 125 kWh/ton hydrazine required
Atofina-PCUK: No byproducts; >80% yield (based on NH
3
); 16 kWh/ton hydrazine required
Hydrazine in the Wonderful World Around Us
•
Free hydrazine on the Earth is not known (because of air oxidation), but was assumed to be
present in the primordial environment.
•
One major application of hydrazine today is as a rocket fuel (along with methylhydrazine as
well). First developed by Germany for powering prototype jet engines in the Messerschmitt
ME163 (WWII), simple hydrazines are still in use today by NASA for specific applications
requiring certain types of thrust. For example, the International Space Station uses
dimethylhydrazine for propulsion to maintain orbit and control attitude.
•
Aside from pesticides and pharmaceuticals, the other major hydrazine application is in the
deoxygenation of boiler feed water. This decomposition is catalyzed by metals such as
copper and cobalt, and most likely also by metallic species leached gradually from pipe
systems (especially nickel).
H
2
NNH
2
+ O
2
N
2
+ 2 H
2
O
Naturally Occurring Hydrazines
N
Me
N
O
H
H
Gyromitrin, from the false morel
mushroom,
Gyromitra esculenta
HO
O
NH
2
H
N
O
N
H
OH
Agaritine, from the N.A. commercial
mushroom,
Agaricus bisporus,
777
million lbs. grown in 1996
H
2
N
OH NH
2
H
N
O
N
CH
3
OH
O
Negamycin, antibiotic from
Streptomyces purpeofuscus
N
HN
CH
3
O
NH
2
OH
O
Linatine, found in linsead
meal and flax
Some Synthetic Hydrazines with Useful Properties
N
O
NHNH
2
Isoniazid (TB)
N
O
N
H
H
N
Iproniazid (early antidepressant,
but toxic)
N
N
NHNH
2
Hydralazine
(antihypertensive)
N
N
F
3
C
SO
2
NH
2
Celebrex
(NSAID)
N
N
N
NH
2
SMe
O
Sencor
(Herbicide)
NH
NH
O
O
Maleic hydrazide
(plant growth retardant)
Maleic hydrazide is marketed under the amusing trade names Slo-Gro, Royal Slow-Gro, Slows-It,
De-Sprout, De-Cut, Fair Plus, Sprout Stop, and Super Sucker-Stuff
The Woes of Hydrazine Alkylation
Direct alkylation of hydrazine is problematic for the same reason that direct alkylation of
primary amines is problematic: overalkylation is competitive with monoalkylation.
H
2
N
NH
2
RX
Base
HN
NH
2
N
NH
2
N NH
2
+
+
R
R
R
R
R
R
X
-
Whoa!
H
2
N
NH
2
CD
3
I
Base
HN
NH
2
N
NH
2
+
CD
3
CD
3
D
3
C
HN
NH
CD
3
CD
3
+
56.1%
42.4%
1.5%
Anthoni, U.; Larsen, C.; Nielsen, P.H.
Acta Chem. Scand.
,
1968
,
22
, 1025-1035.
Direct Alkylation
Can
Sometimes Be Feasible…
Direct alkylation can occasionally be feasible if (1) the electrophile is very bulky; (2) the
electrophile contains an EWG; or (3) an activated alkene is used.
H
2
N
NH
2
Ph
3
CCl
N
H
NH
2
Ph
3
C
H
2
N
NH
2
EWG
R
H
2
N
H
N
R
EWG
H
2
N
NH
2
X
R
O
N
H
NH
2
R
O
(1)
(2)
(3)
Some Strategies for Monsubstituted Hydrazines
These procedures are invariably reliant on protecting groups of one
form or another. An important limitation is that only activated
primary
electrophiles are viable in these reactions.
HN NH
2
Ph
2
OP
RBr/PTC
NaOH
N NH
2
Ph
2
OP
R
HCl
N NH
2
H
R
HN N
Boc
Bu
4
NHSO
4
, KOH
RBr, PhCH
3
, 80
o
C
N N
Boc
R
2N HCl (2 eq.)
THF, reflux, 3h
N NH
2
H
R
N
O
O
NH
Boc
Ph
3
P, DEAD
ROH
N
O
O
N
Boc
R
MeNHNH
2
H
2
N N
Boc
R
TFA
H
2
N N
H
R
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
Meyer, K. G.
Synlett
,
2004
,
13
, 2355-2356.
More on Monosubstitution
Reductions of hydrazones and hydrazides also leads to monosubstituted
hydrazines, including ones with secondary alkyl groups.
R
1
R
2
O
H
2
NNH
2
R
1
R
2
N NH
2
H
2
/cat. or
NaCNBH
3
, etc.
R
1
R
2
H
N NH
2
H
N NH
2
R
O
LAH/AlCl
3
H
N NH
2
R
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
1,1-Disbustituted Hydrazines
HN NH
2
R
1
R
2
X
N NH
2
R
1
R
2
N H
R
1
R
2
1) Nitrosation
2) Reduction
N NH
2
R
1
R
2
N H
R
1
R
2
H
2
N-X
X = -Cl, -OSO
3
H
N NH
2
R
1
R
2
N H
R
1
R
2
N
O
R
P
+
N NH
R
1
R
2
P
Deprotection
N NH
2
R
1
R
2
More on that oxaziridine later…
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
1,2-Disubstituted Hydrazines
A bit more troublesome than the 1,1-disubstituted case:
N NH
2
H
Ph
2
OP
R
1
Br/PTC
N NH
2
R
1
Ph
2
OP
N N
R
1
Ph
2
OP
H
Ac
AcCl
R
2
Br/PTC
HCl
N N
R
1
Ph
2
OP
R
2
Ac
N N
H
R
1
H
R
2
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
“Higher” Hydrazines?
No pain, no gain!
N N
Cbz
H
H
H
TsCl, pyr,
98%
N N
Cbz
H
Ts
H
N N
Cbz
H
Ts
Boc
Boc
2
O, DMAP,
MeCN, 99%
BnBr, K
2
CO
3
, TBAHS,
MeCN, 3 d, quant.
N N
Cbz
PhH
2
C
Ts
Boc
Mg, MeOH,
sonication, 98%
N N
Cbz
PhH
2
C
H
Boc
MeI, K
2
CO
3
-NaOH,
TBAHS, PhH, quant.
N N
Cbz
PhH
2
C
CH
3
Boc
1) TFA, DCM, 93-99%
2)
p
-FC
6
H
4
COCl, pyr., 99%
N N
Cbz
PhH
2
C
CH
3
O
p
-FC
6
H
4
1) TFA (reflux)
2)
p
-FC
6
H
4
SO
2
Cl, 72%
N N
p
-FC
6
H
4
SO
2
PhH
2
C
CH
3
O
p
-FC
6
H
4
Grehn, L.; Lönn, H.; Ragnarsson, U.
Chem. Commun.
,
1997
, 1381-1382.
Greahn, L.; Nyasse, B.; Ragnarsson, U.
Synthesis
,
1997
, 1429-1432.
Incorporation of Secondary Alkyl Groups
Using the same triprotected starting material, a single branched substituent can be introduced first by
the usual condensation/reduction sequence. Surprisingly, the orthogonally
N,N
-diprotected motif
was apparently unknown before this time.
N N
Cbz
H
Ts
Boc
H
2
/ 5% Pd/C,
MeOH, 81%
N N
H
H
Ts
Boc
1) neat acetone, 81%
2) NaBH
4
, THF/EtOH
N N
Ts
Boc
H
Grehn, L.; Ragnrasson, U.
Tetrahedron
,
1999
,
55
, 4843-4852.
The Oxaziridine…
The oxaziridine reagent can be used to prepare Boc-protected peptidomimetics, but the
reaction is hampered by a facile side reaction. This can be overcome by utilizing
protected amino acids (but proline works OK by itself!).
NC
N
O
Boc
R
1
NH
CO
2
H
R
2
+
R
1
N
CO
2
H
R
2
NH
Boc
NC
CHO
+
R
1
NH
CO
2
H
R
2
R
1
N
CO
2
H
R
2
CN
Side
Reaction!
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
An Unusual Approach
Some trisubstituted hydrazines can be accessed by displacement of a
benzotriazole moiety.
HN NH
Ph
Ph
+ R
1
CHO +
N
H
N
N
DCM, rt, 3 A mol. sieves or
PhH, reflux, Dean-Stark
N NH
Ph
Ph
N
R
1
N
N
N NH
Ph
Ph
N
R
1
N
N
+
R
2
MgX
0
o
C --> RT
N NH
Ph
Ph
R
2
R
1
X
ZnBr
N NH
Ph
Ph
X
R
1
= H
R
1
= H, Et,
n
-Pr, cyclohexyl
R
2
= Et, Ph, allyl
X = O, 62%
X = S, 53%
68-99%
Ragnarsson, U.
Chem. Soc. Rev.
2001
,
30
, 205-213.
Katritzky, A. R.; Qiu, G.; Yang, B.
J. Org. Chem.
1997
,
62
, 8210-8214.
Isoniazid Studies: Hydrazines in Action
To study the mechanism of action of Isoniazid,
15
N labeled analogs were required.
Here, the hydrazine was made by an electophilic amination protocol.
N*
O
O
K
+
O
2
N
NO
2
ONH
2
+
N*
O
O
NH
2
DMF, rt,
1h, 88%
4-C
6
H
4
NCO
2
H, CO(Im)
2
,
THF, reflux, 60 h, 78%
N*
O
O
H
N
O
N
N
2
H
4
, H
2
O,
15 min, rt, 70%
N
CONHN*H
2
Isoniazid
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
Brosse, N.; Pinto, M. F.; Jamart-Gregoire, B.
J. Chem. Soc. Perkin Trans, 1
,
1998
, 3685-3688.
Isoniazid Continued…
Preparation of the other singly labeled Isoniazid…
N*
O
O
Boc
2
O, DMAP,
Et
3
N,THF, rt, 65%
NH
2
N*
O
O
N
Boc
Boc
H
2
NNH
2
, EtOH/H
2
O,
- 20
o
C, 2 h, 87%
N* N
Boc
Boc
H
H
4-C
6
H
4
N-CO
2
H, CO(Im)
2
,
THF, reflux, 72 h, 75%
N
CON*HN(Boc)
2
3 M HCl, AcOEt,
quant.
N
CON*HNH
2
2 HCl
Isoniazid (HCl salt)
Ragnarsson, U.
Chem. Soc. Rev.,
2001
,
30
, 205-213.
Brosse, N.; Pinto, M. F.; Jamart-Gregoire, B.
J. Chem. Soc. Perkin Trans, 1
,
1998
, 3685-3688.
The Beginning of the Myers TBS-Tosylhydrazones
A one-pot hydrazone preparation is followed by conversion to an
E
olefin with overall apparent
olefin migration. Note that prior to silylation, the tosylhydrazone typically undergoes 1,4-addition
of organolithiums rather than 1,2-addition.
CH
3
N
H
NH
Ts
TBSOTf, NEt
3
,
THF, -78
o
C
CH
3
N
H
N
Ts
TBS
CH
3
O
H
TsNHNH
2
THF, RT
(in one
pot)
1)
n
-BuLi, THF, -78
o
C
2) AcOH, CF
3
CH
2
OH,
-20
o
C
CH
3
CH
3
CH
3
CH
3
+
E
:
Z
= 12:1
Myers, A. G.; Kukkola, P. J.
J. Am. Chem. Soc.
1990
,
112
, 8208-8210.
So what’s the mechanism? Not this one!
CH
3
N
H
N
Ts
TBS
CH
3
HN
N
Ts
TBS
CH
3
1)
n
-BuLi
2) AcOH
Attempted
workup
CH
3
HN
N
S
CH
3
OTBS
O
PhCH
3
Stable to chromatography
HF
.
Et
3
N
CH
3
HN
NH
Ts
CH
3
X
CH
3
CH
3
No product formation under the reaction
conditions, but slow formation at RT with
lower stereoselectivity
Myers, A. G.; Kukkola, P. J.
J. Am. Chem. Soc.
1990
,
112
, 8208-8210.
The More Likely Mechanism
CH
3
CH
3
N
H
N
Ts
TBS
CH
3
HN
N
Ts
TBS
CH
3
1)
n
-BuLi
2) AcOH
- HO
2
SPhCH
3
CH
3
N
N
TBS
CH
3
CH
3
H
H
N
HN
Minimal
A
1,3
strain
CH
3
H
N
HN
H
CH
3
Not-so-minimal
A
1,3
strain
Protodesilylation
E
-isomer
Z
-isomer
Myers, A. G.; Kukkola, P. J.
J. Am. Chem. Soc.
1990
,
112
, 8208-8210.
And Some Examples
Where A
1,3
strain begins to diminish, A
1,2
strain can start taking over:
H
3
C
CHO
CH
3
CH
3
1) Hydrazone formation
2)
Li
Et
H
3
C
CH
3
CH
3
CH
3
Et
90% (
E
:
Z
= 2:1)
via:
R
H
H
N NH
Et
vs.
H
H
N NH
Et
R
H
3
C
CHO
CH
3
CH
3
1) Hydrazone formation
2)
Li
CH
3
H
3
C
CH
3
CH
3
Et
CH
3
83% (
E
:
Z
> 20:1)
CH
3
via:
R
H
CH
3
N NH
CH
3
vs.
H
CH
3
N NH
CH
3
R
Myers, A. G.; Kukkola, P. J.
J. Am. Chem. Soc.
1990
,
112
, 8208-8210.
And a Few Hindered Cases
Importantly, no racemization occurs with nonracemic aldehyde precursors.
O
O
O
O
O
CHO
H
3
C
CH
3
H
3
C
CH
3
1) Hydrazone formation
2)
Li
CH
3
CH
3
O
O
O
O
O
H
3
C
CH
3
H
3
C
CH
3
CH
3
CH
3
O
O
O
O
O
CHO
H
3
C
CH
3
H
3
C
CH
3
1) Hydrazone formation
2)
Li
O
O
O
O
O
H
3
C
CH
3
H
3
C
CH
3
O
O
O
O
O
CHO
H
3
C
CH
3
H
3
C
CH
3
1) Hydrazone formation
2)
Li
Et
O
O
O
O
O
H
3
C
CH
3
H
3
C
CH
3
n-
Pr
CH
3
CH
3
81% (
E:Z
>20:1)
86% (
E:Z
>20:1)
79% (
E:Z
= 1:1)
Myers, A. G.; Kukkola, P. J.
J. Am. Chem. Soc.
1990
,
112
, 8208-8210.
How About Some Saturation?
If both the hydrazone and the lithium reagent are saturated, then you can get a
nice, reductive coupling for a net C-C (sp
3
-sp
3
) bond formation.
Ph
N
H
NTBS
Ts
CH
3
Li
Ph
CH
3
CH
3
H
3
CCH
3
1)
, -78
o
C, THF
2) AcOH, TFE,
-78
o
C --> RT
94%
Ph
LiN
NTBS
Ts
CH
3
t
-BuLi
CH
3
H
3
CCH
3
AcOH, TFE
Ph
N
N
H
CH
3
CH
3
H
3
CCH
3
Ph
CH
3
CH
3
H
3
CCH
3
+ N
2
Myers, A. G.; Movassaghi, M.
J. Am. Chem. Soc.
1998
,
120
, 8891-8892.
Evidence for Those Radicals…
…comes from TEMPO trapping and fragmentation of a cyclopropyl group.
Ph
H
N
N
TBS
Ts
1)
n
-BuLi, THF, -78
o
C
2) AcOH, TFE, TEMPO
-78
o
C --> RT
Ph
O
N
H
3
C
CH
3
CH
3
CH
3
CH
3
93%
Ph
H
N
N
TBS
Ts
t
-BuLi
Ph
CH
3
H
3
C CH
3
83%
Myers, A. G.; Movassaghi, M.
J. Am. Chem. Soc.
1998
,
120
, 8891-8892.
But There Can Be Competition for Radical vs. [1,5]
H-Shift Pathways
As with the previous olefin coupling, when pendant unsaturation is appropriately positioned within
the molecule, the [1,5] H-shift can be operative (and is preferred).
N
H
N
TBS
Ts
N
N
H
CH
3
1)
n
-BuLi, -78
o
C
2) AcOH, TFE,
-78
o
C --> RT
X
CH
3
[1,5]
CH
3
81%
CH
3
N
HN
H
- N
2
Myers, A. G.; Movassaghi, M.
J. Am. Chem. Soc.
1998
,
120
, 8891-8892.
Some Examples of the Reductive Coupling
O
O
O
O
O
H
3
C
CH
3
H
3
C
CH
3
H
N
N
Ts
TBS
O
O
O
O
O
H
3
C
CH
3
H
3
C
CH
3
R
RLi
R =
t
-Bu, 87%
R = Ph, 78%
Ph
Li
CH
3
CH
3
CH
3
Ph
H
N
N
TBS
Ts
CH
3
+
Ph
CH
3
Ph
CH
3
CH
3
CH
3
94%
Ph
H
N
N
TBS
Ts
+
OLi
N
CH
3
CH
3
THF, -20
o
C
Ph
N
CH
3
CH
3
O
97%
Even an amide enolate is basic enough for this protocol, but
lithium acetylides and Grignard reagents are not.
Myers, A. G.; Movassaghi, M.
J. Am. Chem. Soc.
1998
,
120
, 8891-8892.
Some
Limitations
of the Reductive Coupling
Very bulky nucleophiles work OK, but the reaction does suffer when bulky
hydrazones are used. Fortunately, a solution to the problem is available.
H
N N Ts
n
-BuLi
H
N N S
H
O
O
CH
3
TBS
+
39%
52%
H
N N SO
2
Ar
Ar = 2,4,6-triisopropylbenzene
n
-BuLi
95%
TBS
TBS
Myers, A. G.; Movassaghi, M.
J. Am. Chem. Soc.
1998
,
120
, 8891-8892.
An Example from the World of Synthesis
A late-stage usage of Myers’ coupling chemistry was planned as shown below.
Unfortunately, it failed in this case, and a lengthier route was needed.
R
2
O
OR
2
H
H
H
R
1
O
N
H
N
SO
2
Ar
TBS
Ar = ?
Li
R
2
O
OR
2
H
H
H
R
1
O
X
R
1
= TBS, R
2
= Me
R
1
= TBS, R
2
= Me
R
1
= H, R
2
= SO
3
Na, Adociasulfate 1
Bogenstätter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L.
J. Am. Chem. Soc.
1999
,
121
, 12206-7.
And Another!
OH
HO
HO
OH
(-)-Cylindrocyclophane F
I
OMe
MeO
MeO
OMe
MOMO
N
N
H
3
CPhO
2
S
TBS
+
RCM
Myers reductive alkylation
In the forward direction, this transformation, along with MOM deprotection,
proceeded in a combined 73% yield. Subsequent RCM and further deprotections
led nicely to the natural product.
Smith, A. B.; Kozmin, S. A.; Paone, D. V.
J. Am. Chem. Soc.
1999
,
121
, 7423-4.
Wolff-Kishner Revisited
R
1
R
2
O
R
1
R
2
In the original procedure (1911), preformed hydrazones were added to hot, solid KOH, or heated
with NaOEt in EtOH in a sealed tube at 160-200 ºC. The most common modification now in use is
the Huang-Minlon version, which calls for heating the carbonyl compound with hydrazine and alkali
in a high-boiling ethereal solvent at ~ 200 ºC. Obviously, milder conditions for this classic
transformation would be of value.
Kishner, N.
Zh. Russ. Fiz.-Khim. O-va., Chast. Khim.
1911
,
43
, 582.
Huang-Minlon.
J. Am. Chem. Soc.
1946
,
68
, 2487.
The Mechanism
N
R
R
NH
2
+ B
-
M
+
N
R
R
NH M
+
+ B-H
N
R
R
NH M
+
B'-H +
+ nS
*
B'
N
R
R
N
H
M
+
+
+ H
+
(S)
n
N
R
R
N
H
fast
C
H
R
R
+ N
2
C
H
R
R
fast
+ B-H
H
2
CR
2
+ B
-
B' + H
+
(S)
n
fast
B'-H + nS
Szmant, H. H.
Angew. Chem. Int. Ed.
1968
,
7
, 120-128.
More Woes of the Traditional Wolff-Kishner
R
H
O
H
2
NNH
2
R
H
N
NH
2
SiO
2
, moisture,
or just sitting around
R
H
N
N
H
R
Azine!
A major drawback of the Wolff-Kishner reduction is the competitive formation of the azine
byproduct. This is particularly problematic for aldehyde hydrazones, with many hydrazones having
lifetimes only on the order of several hours. Since silyl groups are often “proton surrogates,” using
a TBS-protected hydrazone instead would seem to be a good idea, but these compounds are not
formed as easily as one might think:
H
2
N NH
TBS
2
HN NH
TBS
TBS
+ H
2
NNH
2
R
1
N
R
2
H
N
TBS
R
1
N
R
2
NH
2
R
1
N
R
2
N
R
2
R
1
+
+
H
2
N NH
TBS
R
1
O
R
2
Bode, K.; Klingebiel, U.
Adv. Organomet. Chem.
1996
,
40
, 1.
The More TBS the Merrier: A Simple Alternative
R
1
R
2
O
N N
H
TBS
H
TBS
0.01 mol% Sc(OTf)
3
,
neat, 0
o
C --> RT
R
1
R
2
N
N
H
TBS
+ TBSOH
(BTBSH)
•BTBSH is
less
nucleophilic than TBS-hydrazine, but Sc(OTf)
3
compensates for this.
•The TBSOH byproduct formed is less nucleophilic than the H
2
O produced when TBS-hydrazine is
employed, thereby preventing self-hydrolysis of the hydrazine.
•BTBSH is
not
prone to disproportionation like the TBS-hydrazine.
•TBSOH is volatile enough to be removable under vacuum, and excess BTBSH doesn’t affect later
chemistry, so purification after this step is usually unnecessary.
•
The product hydrazones are indefinitely stable when properly stored.
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
A Few Examples
H
O
H
OBz
O
O
BTBSH, 0.01 mol% Sc(OTf)
3
,
DCM
H
N
H
OBz
O
O
N
H
TBS
>95%
N
O
OH
OH
O
HCl 2H
2
O
Ph
H
O
BTBSH, 0.01 mol% Sc(OTf)
3
,
neat
Ph
H
N
N
H
TBS
>95%
N
O
OTBS
OH
N N
TBS
H
BTBSH, 1 mol% Sc(OTf)
3
,
CHCl
3
91%
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
And Now: A Modified Wolff-Kishner Reduction
PhO
H
O
1) BTBSH, cat. Sc(OTf)
3
2) KO
t
-Bu, HO
t
-Bu,
DMSO, 100
o
C, 24 h
PhO
CH
3
92%; 96% "without
evacuation"
PMP
CH
3
O
1) BTBSH, cat. Sc(OTf)
3
2) KO
t
-Bu, HO
t
-Bu,
DMSO, RT, 24 h
PMP
CH
3
94%; 93% "without
evacuation"
O
CH
3
H
3
C
H
H
H
H
H
CH
3
H
HO
CH
3
O
1) BTBSH, cat. Sc(OTf)
3
2) KO
t
-Bu, HO
t
-Bu,
DMSO, RT or 100
o
C, 24 h
O
CH
3
H
3
C
H
H
H
H
H
CH
3
H
RO
CH
3
RT: R=TBS, 91%; 91% "without
evacuation"
100
o
C: R=H, 95%; 96%
"without evacuation"
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
What About A Direct Comparison?
In this complex setting, the modified conditions gave a yield ~15%
higher than the traditional Wolff-Kishner conditions.
O
CH
3
H
3
C
H
H
H
H
H
CH
3
H
HO
CH
3
O
1) BTBSH, cat. Sc(OTf)
3
2) KO
t
-Bu, HO
t
-Bu,
DMSO, 100
o
C, 24 h
O
CH
3
H
3
C
H
H
H
H
H
CH
3
H
HO
CH
3
A: 95%; 96% "without
evacuation"
B: 79%
A
B
OR
H
2
NNH
2
, KOH,
diethylene glycol, 195
o
C
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
Iodides, Anyone?
Barton reported these new reactions of hydrazones in 1962:
HO
CH
3
CH
3
O
HO
CH
3
CH
3
I
1) H
2
NNH
2
2) I
2
, Et
3
N
O
H
1) H
2
NNH
2
2) I
2
, Et
3
N
I
I
70%
Barton, D. H. R.; O’Brien, R. E.; Sternhell, S.
J. Chem. Soc.
1962,
470-476.
A Useful Mechanistic Dichotomy
Here’s a mechanistic picture for their formation:
N
R
NH
2
I
2
, Et
3
N
N
R
N
I
H
- HI
N
R
N
"I
+
"
N
R
N
I
- N
2
I
R
R'
R'
R'
R'
R'
H
-H
+
I
-
I
R
R'
I
R
R'
I
Depending on the availability of
β
-hydrogens, either vinyl
iodides or
gem
-diiodides (or mixtures) are obtainable.
Barton, D. H. R.; O’Brien, R. E.; Sternhell, S.
J. Chem. Soc.
1962,
470-476.
More Bang for the Buck for the TBS Hydrazones
If the TBS hydrazones work for Wolff-Kishner reactions, then
why not for the Barton iodide reactions?
Br
O
1) BTBSH, cat. Sc(OTf)
3
2) Slow add'n to THF soln. of
I
2
and TMG at 0
o
C
Br
I
85%
N
O
OH
OH
O
HCl 2H
2
O
1) BTBSH, cat. Sc(OTf)
3
2) Slow add'n to THF soln. of
I
2
and TMG at 0
o
C
N
O
OH
OH
I
84%
tetrasub. : trisub. = 57:43
PMP
O
1) BTBSH, cat. Sc(OTf)
3
2) Slow add'n to THF soln. of
I
2
and TMG at 0
o
C
PMP
PMP
PMP
I
I
I
62 : 17 : 21
71%
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
As for the
Gem-
Diiodides…
These reactions are serviceable as well, even where
competitive vinyl iodide formation is possible.
Ph
H
O
1) BTBSH, 0.01 mol% Sc(OTf)
3
2) I
2
, Et
3
N, MeOH, THF, -10
o
C --> RT
Ph
I
I
64%
H
O
H
OBz
O
O
1) BTBSH, 0.01 mol% Sc(OTf)
3
2) I
2
, Et
3
N, MeOH, THF, -10
o
C --> RT
I
I
H
OBz
O
O
62%
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
Other Halides Needn’t Be Left Out!
PMP
H
O
1) BTBSH, 0.01 mol% Sc(OTf)
3
2) CuCl
2
, Et
3
N, MeOH, THF, -10
o
C --> RT
PMP
Cl
Cl
86%
1) BTBSH, 0.01 mol% Sc(OTf)
3
2) CuBr
2
, Et
3
N, MeOH, THF, -10
o
C --> RT
76%
O
O
O
H
3
C
H
3
C
Br
O
O
H
3
C
H
3
C
O
O
H
3
C
H
3
C
Br
Br
O
O
O
H
3
C
H
3
C
1) BTBSH, 0.01 mol% Sc(OTf)
3
2) Br
2
, BTMG, CH
2
Cl
2
, RT
65% (with 7%
dibromide)
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 5436-5445.
And for Something Completely Different…
Esterification with in-situ generated diazoalkanes!
R
R'
N
N
H
TBS
2-chloropyridine, CH
2
Cl
2
,
-78
o
C
I
F
F
Ph
R
R'
N
N
HO
R''
O
O
R''
O
R
R'
-78
o
C --> RT
Two simple examples:
Ph
H
O
HO
O
PMP
1.5 eq.
O
O
PMP
Ph
86%
HO
O
Br
H
3
CO
H
3
CO
H
O
1.5 eq.
O
O
Br
H
3
CO
H
3
CO
90%
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 12222-12223.
And Finally, A Few More Examples
H
O
H
OBz
O
O
3 eq.
NO
2
HO
O
NO
2
O
O
H
OBz
O
O
84%
OH
H
H
3
C
HO
O
O
CO
2
H
H
3
CO
H
3
CO
NO
2
O
H
3 eq.
OH
H
H
3
C
HO
O
O
O
O
O
2
N
OCH
3
OCH
3
82%
CO
2
H
HO
2
C
HO
2
C
CO
2
H
CO
2
H
CO
2
H
H
2
O
O
H
18 eq.
CO
2
Bn
BnO
2
C
BnO
2
C
CO
2
Bn
CO
2
Bn
CO
2
Bn
53%
Furrow, M. E.; Myers, A. G.
J. Am. Chem. Soc.
2004
,
126
, 12222-12223.
