Preparation and deprotection of aldehyde dimethylhydrazones

Article abstract of DOI:10.1080/00397910600616776

Aldehydes were conveniently protected as dimethylhydrazones by stirring a mixture of the aldehyde, N,N-dimethylhydrazine, anhydrous magnesium sulfate, and dichloromethane at room temperature. Azeotropic removal of water, formed during the course of the reaction, was not required because anhydrous magnesium sulfate functions as a water scavenger. Deprotection of aldehyde dimethylhydrazones was accomplished by stirring a mixture of the aldehyde dimethylhydrazone and aqueous glyoxylic acid at room temperature. The reaction time for the preparation and deprotection of aldehyde dimethylhydrazones varied with the structure of the aldehyde. Copyright Taylor & Francis Group, LLC.

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Preparation and Deprotection of Aldehyde
Dimethylhydrazones
Richard J. Petroski a
a United States Department of Agriculture, Research Education and
Economics, Agricultural Research Service, National Center for Agricultural
Utilization Research, Crop Bioprotection Research Unit, Peoria, Illinois, USA
Published online: 22 Aug 2006.
To cite this article: Richard J. Petroski (2006) Preparation and Deprotection of Aldehyde Dimethylhydrazones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:12, 1727-1734
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Synthetic Communicationsw, 36: 1727–1734, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600616776
Preparation and Deprotection of Aldehyde
Dimethylhydrazones
Richard J. Petroski
United States Department of Agriculture, Research Education and
Economics, Agricultural Research Service, National Center for
Agricultural Utilization Research, Crop Bioprotection Research Unit,
Peoria, Illinois, USA
Abstract: Aldehydes were conveniently protected as dimethylhydrazones by stirring a
mixture of the aldehyde, N,N-dimethylhydrazine, anhydrous magnesium sulfate, and
dichloromethane at room temperature. Azeotropic removal of water, formed during
the course of the reaction, was not required because anhydrous magnesium sulfate
functions as a water scavenger. Deprotection of aldehyde dimethylhydrazones was
accomplished by stirring a mixture of the aldehyde dimethylhydrazone and aqueous
glyoxylic acid at room temperature. The reaction time for the preparation and deprotec-
tion of aldehyde dimethylhydrazones varied with the structure of the aldehyde.
Keywords: Aldehyde dimethylhydrazones, aqueous glyoxylic acid, deprotection,
N,N-dimethylhydrazine, prepartion
INTRODUCTION
Protection of carbonyl compounds as dimethylhydrazones is a common
practice[1] that enables the synthesis of spiroacetal compounds via
metalated hydrazones,[2] the conversion of aldehydes to nitriles,[3] and the
Received in the USA December 14, 2005
The mention of trade names or commercial products in this article is solely for the
purpose of providing specific information and does not imply recommendation or
endorsement by the U.S. Department of Agriculture.
Address correspondence to Richard J. Petroski, United States Department of
Agriculture, Research Education and Economics, Agricultural Research Service,
National Center for Agricultural Utilization Research, Crop Bioprotection Research
Unit, 1815 N. University Street, Peoria, IL 61604, USA. Fax: (309) 681-6693;
E-mail: petrosrj@mail.ncaur.usda.gov
1727

1728
R. J. Petroski
conversion of aldehydes to a,b-unsaturated aldehydes via silyl aldehyde
dimethylhydrazones.[4]
Deprotection of ketone dimethylhydrazones occurs readily under very mild
conditions (e.g., wet silica gel in THF);[5] however, deprotection of aldehyde
dimethylhydrazones is more difficult because nitriles can be formed by loss of
dimethylamine.[3] Aldehyde deprotection conditions have been developed that
rely on conversion of the aldehyde dimethylhydrazones to the methiodide and
then stirring with a mixture of 5% aqueous HC1,[4] but these conditions
would not be suitable for acid-labile unsaturated aldehydes. A more recent
method utilized aqueous CuCl2 in THF;[6] however, attempts to deprotect
diene aldehyde dimethylhydrazones resulted in large amounts (about 20%) of
a mixture of unknown side products. Aldehyde oximes can be deprotected by
50% aqueous glyorylic aci,[7] and investigation found that 50% aqueous
glyoxylic acid could also be used to deprotect aldehyde dimethylhydrazones.
Improved methods for the preparation of aldehyde dimethylhydrazones
and deprotection of aldehyde dimethylhydrazones are presented in this
article (Table 1). Although existing methods for the preparation[1] and depro-
tection[1,6] of aliphatic or aromatic aldehyde dimethylhydrazones are usually
sufficient, these methods do not work well for some unsaturated aldehyde
dimethylhydrazones.
The synthetic utility of dimethylhydrazone derivatives of aldehydes,
especially unsaturated ones, should be enhanced as a result of this report.
Alkyl halides can be converted to aldehydes with extension of the carbon
chain by two carbons with acetaldehyde dimethylhydrazone.[4] Alkylation at
the a-position of 3-methyl-2-butenal dimethylhydrazone, along with double
bond migration from the a,b-position to the b,g-position, was utilized in a
concise synthesis of lavandulol.[6]
EXPERIMENTAL
Preparation of Aldehyde Dimethylhydrazones
Aldehydes were protected as dimethylhydrazones by stirring a mixture of
the aldehyde (1 mmol), N,N-dimethylhydrazine (1.3 mmol), anhydrous
magnesium sulfate (2 mmol), and dichloromethane (3 mL) at room tempera-
ture. After gas chromatography (GC) analysis indicated the complete conver-
sion of starting aldehyde to product, the reaction mixture was filtered and the
solvent and unreacted N,N-dimethylhydrazine were removed by rotary evap-
oration at water aspirator pressure to afford the aldehyde dimethylhydrazone
with a purity ranging between 96% and 99%, which reflected the purity of the
starting aldehyde. The only exception was the preparation of the dimethylhy-
drazone derivative of (2E,4E)-2,4-dimethylhexadienal, which resulted in a
mixture composed of 85% of the desired product along with 15% of
unreacted starting material after 96 h. The product, from a 10-mmol

Aldehyde Dimethylhydrazones
1729
Table 1. Preparation and deprotection of aldehyde dimethylhydrazones
Entry
1
Aldehydes
Aldehyde dimethylhydrazones
CH3-(CH2)6-CH55N-N(CH3)2
CH3-(CH2)6-CHO
2
3
4
5
6
scale synthesis, can be easily separated from unreacted starting material by
Kugelrohr distillation. After distillation, the purity of N0-(2,4-dimethyl-
hexa-2,4-dienylidene)-N,N-dimethyl-hydrazine (bp 388C at 0.05 Torr) was 98%.
Deprotection of Aldehyde Dimethylhydrazones
Deprotection was accomplished by stirring a solution containing the aldehyde
dimethylhydrazone (1 mmol) and 50% aqueous glyoxylic acid (2 mL) at room
temperature. The course of each reaction was followed by GC. For analysis, an

1730
R. J. Petroski
aliquot of the reaction mixture (25 mL) was added to a Teflonw-lined screw-
capped vial containing hexane (3 mL) and water (0.5 mL); then the resulting
mixture was shaken, and the phases were allowed to separate. The hexane
phase was transferred to a new vial and dried over anhydrous Na2SO4
before analysis by GC.
Deprotection reactions can be worked up by extraction of the previously
mentioned reaction mixture, followed by extraction with petroleum ether
(bp 35 to 608C 4ꢀ2 mL), washing the combined organic phases with water
(2 mL), drying over anhydrous Na2SO4, filtration, and removal of solvent
by rotary evaporation at water aspirator pressure to afford the free aldehyde.
Purity ranged from 95% to 99% and reflected the purity of the starting
aldehydes brought through the protection and deprotection steps.
Analysis of Reaction Products
Deprotection yields were determined by conversion of starting material to
product as measured by gas chromatography (GC) because some of the
aldehyde products are volatile enough for significant loss to occur during
workup. All reaction products were identified by GC/MS, and the structures
of aldehyde dimethylhydrazones were additionally verified by NMR.
For monitoring reactions by GC, a Hewlett-Packard (HP) 5890 series II
instrument was equipped with flame ionization detector and interfaced to a
HP ChemStation data system. The oven temperature was programmed from
50 to 2808C at 108C/min, the cool on-column inlet tracked the oven tempera-
ture, and the detector temperature was 2808C. A DB-5 capillary column
(30 m ꢀ 0.25 mm, 0.25-mm film thickness, J&W Scientific, Folsom, CA)
was used with 1.0-mL sample injections.
Electro-impact mass spectra (EIMS) (70 eV) were obtained with an HP
5973 MSD instrument, equipped with a splitless injector. The oven tempera-
ture was programmed from 50 to 2508C at 108C/min; the injector temperature
was 2508C, and the detector temperature was 2508C. An EC-1 capillary GC
column (30 m ꢀ 0.25 mm, 0.1-mm film thickness, Alltech, Deerfield, IL)
was used with 1.0-mL sample injections.
1H NMR, 13H NMR, and two-dimensional NMR spectra (CDCl3) were
1
obtained on a Bruker (Bellerica, MA) Avance 400 instrument. H and 2-D
homonuclear one-bond J coupling correlation spectroscopy (COSY) spectra
were acquired at 400 MHz whereas 13C and distortionless enhancement by
polarization transfer (DEPT) spectra were acquired at 100 MHz. Chemical
shifts are referenced to tetramethylsilane; coupling constants (J ) are in hertz.
1
Assignments were made with the help of H- and 13C-Predictive software[8]
and a reference[9] which gave 1H NMR data for similar compounds.
1
Published H NMR data is available[10] for compounds 4 and 5. It is very
unlikely that any of these compounds are new; however, spectral data is
given because such data is very difficult to find in the older chemical literature.

Aldehyde Dimethylhydrazones
1731
Spectral Data for Aldehyde Dimethylhydrazones
N0-Octylidene-N,N-dimethyl-hydrazine (1)
MS (EI) m/z (%) 170 (Mþ, 76), 155 (4), 141 (4), 127 (19), 113 (15), 99 (21),
86 (100), 71 (13), 60 (21), 59 (22), 44 (48). 1H NMR d 0.91 (3H, t, J7–8 ¼ 6.7,
H-8), 1.30–1.33 (8H, m, H-4–H-7), 1.50 (2H, quintet, J2–3 ¼ 7.6 and
J3–4 ¼ 7.0, H-3), 2.25 (2H, q, J1–2 ¼ 5.3 and J2–3 ¼ 7.6, H-2), 2.75 (6H, s,
N-CH3), 6.72 (1H, t, J1–2 ¼ 5.3, H-1). 13C NMR d 14.1 (C-8), 22.6 (C-7), 27.8
(C-3), 29.2 (C-4 and C-5), 31.8 (C-6), 33.1 (C-2) 43.5 (N-CH3), 141.0 (C-1).
N,N-Dimethyl-N0-(2-methyl-pent-2-enylidene)-hydrine (2)
MS (EI) m/z (%) 140 (Mþ, 81), 125 (40), 110 (14), 96 (100), 81 (34), 67 (15),
44 (37). 1H NMR d 1.04 (3H, t, J4–5 ¼ 7.5, H-5), 1.86 (3H, s, CH3 at C-2), 2.23
(2H, quintet, J3–4¼ 7.2 and J4–5 ¼ 7.5, H-4), 2.84 (6H, s, N-CH3), 5.59 (1H,
dd, J2–3 ¼ 0.8 and J3–4 ¼ 7.2, H-3), 7.09 (1H, s, H-1). 13C NMR d 11.5 (C-5),
13.9 (CH3 at C-2), 21.5 (C-4), 43.2 (N-CH3), 133.7 (C-2 and C-3), 135.2 (C-1).
N0-(2,4-Dimethyl-hexa-2,4-dienylidene)-N,N-dimethyl-hydrazine (3)
MS (EI) m/z (%) 166 (Mþ, 16), 151 (80), 137 (17), 121 (100), 106 (62), 79
1
(47), 77 (29), 53 (12), 44 (16), 39 (18). H NMR d 1.75 (3H, d, J5–6 ¼ 6.9,
H-6), 1.86 (3H, s, CH3 at C-4), 2.03 (3H, s, CH3 at C-2), 2.86 (6H, s,
N-CH3), 5.59, (1H, q, J5–6 ¼ 6.9, H-5), 6.01 (1H, s, H-3), 7.08 (1H, s,
H-1). 13C NMR d 13.3 (CH3 at C-2), 13.9 (C-6), 16.6 (CH3 at C-4), 43.2
(N-CH3), 126.2 (C-5), 129.5 (C-4), 132.8 (C-2), 133.8 (C-3), 135.9 (C-1).
N0-Benzylidine-N,N-dimethyl-hydrazine (4)
MS m/z (%) 148 (Mþ, 100), 133, (17), 118 (19), 90 (14), 92 (10), 77 (17), 44
(11). 1H NMR d 3.01 (6H, S, N-CH3), 7.26 (1H, t, J4–5 ¼ 7.6 and J5–6 ¼ 7.6,
H-5), 7.29 (1H, s, H-1), 7.36 (2H, t, J4–5 ¼ 7.6, J5–6 ¼ 7.6, and J3–4 ¼ 7.8,
J6–7 ¼ 7.8, H-4 and H-6), 7.62 (2H, d, J3–4 ¼ 7.8 and J6–7 ¼ 7.8, H-3 and
H-7), 13C NMR d 43.2 (N-CH3), 125.6 (C-3 and C-7), 127.4 (C-5), 128.5
(C-4 and C-6), 132.9 (C-1), 136.9 (C-2).
N,N-Dimethyl-N0-(3-phenyl-allylidene)-hydrazine (5)
MS (EI) m/z (%) 174 (Mþ, 100), 159 (10), 144 (4), 130 (35), 115 (29), 104 (18),
91 (15), 77 (17), 59 (5), 44 (7), 42 (8). 1H NMR d 2.97 (6H, S, N-CH3), 6.66
(1H, d, J2–3 ¼ 15.9, 1 H-3), 6.99 (1H, dd, J1–2 ¼ 7.3 and J2–3 ¼ 15.9, H-2),
7.26 (1H, d, J1–2 ¼ 7.3, H-1), 7.30 (1H, t, J6–7 ¼ 7.1 and J7–8 ¼ 7.1, H-7),
7.35 (2H, t, J6–7 ¼ 7.1, J7–8 ¼ 7.1, and J5–6 ¼ 8.3, J8–9 ¼ 8.3, H-4
and H-6), 7.45 (2H, d, J5–6 ¼ 8.3 and J8–9 ¼ 8.3, H-5 and H-9). 13C NMR

1732
R. J. Petroski
d 42.8 (N-CH3), 126.2 ((C-5 and C-9), 127.4 (C-7), 127.5 (C-2), 128.7 (C-6 and
C-8), 131.8 (C-3), 135.2 (C-1), 137.3 C-4).
N,N-Dimethyl-N0-(2-methyl-3-phenyl-allylidene)-hydrazine (6)
MS (EI) m/z (%) 188 (Mþ, 100), 173 (38), 144 (44), 129 (26), 115 (58),
1
91 (32), 77 (7), 59 (7), 44 (11). H NMR d 2.18 [(3H, s, CH3 at C-2), 2.95
(6H, s, N-CH3), 6.58 (1H, S, H-3), 7.20, s, H-1], 7.30 (1H, m, H-7),
7.39–7.40 (4H, m, H-6, H-8 and H-5, H-9). 13C NMR d 13.4 (CH3 at C-2),
43.1 (N-CH3), 126.5 (C-7), 128.2 (C-5 and C-9), 129.1 (C-6 and C-8),
131.2 (C-3), 131.8 (C-2), 136.0 (C-1), 137.9 C-4).
RESULTS AND DISCUSSION
Aldehydes were conveniently protected as dimethylhydrazones (Table 1),
without the need for azeotropic removal of water[11] from the reaction
mixture, because anhydrous magnesium sulfate scavenges water as it is
formed during the reaction. The reaction conditions are extremely mild and
result in a high yield of product (Table 2) Isolated yields were at least 98%
after 20 h, except the reaction of (2E, 4E)-2,4-dimethyl-2,4-hexadienal,
which yielded only 85% when terminated after 4 days.
The structures of aldehyde dimethylhydrazones were verified by EIMS and
NMR spectrometry. The MS data showed the expected product molecular
weight and the characteristic peak at m/z 44, corresponding to the loss of the
-N(CH3)2 group. The aliphatic aldehyde dimethylhydrazone, derived from
octanal, showed the expected base peak at m/z 86%.[12] The 1H NMR peak at
d 2.75–3.01 (6H, s) is consistent for the expected chemical shift for the
N(CH3)2 protons,[8,9] and the 13C NMR peak at d 42.8–43.5 is also consistent
with the expected chemical shift for the N(CH3)2 group carbons.[8]
Table 2. Preparation and deprotection of aldehyde dimethylhydrazones (DMH)a
Yield of
DMH
Deprotection
yield
Entry
Aldehyde
1
2
3
4
5
6
Octanal
98%, 20 h
.99%, 20 h
85%, 96 h
91%, 4 h
84%, 20 h
94%, 30 h
93%, 4 h
91%, 20 h
96%, 48 h
(2E)-2-Methyl-2-pentenal
(2E,4E)-2,4-dimethyl-2,4—hexadienal
Benzaldehyde
.99%, 20 h
98%, 20 h
.99%, 48 h
trans-Cinnamaldehyde
trans-a-Methylcinnamaldehyde
aSee experimental for dimethylhydrazone formation and deprotection reaction
conditions.
Isolated yields are reported.

Aldehyde Dimethylhydrazones
1733
Saturated aldehyde dimethylhydrazones and aromatic aldehyde dimethyl-
hydrazones can be readily deprotected using, previously reported method-
ology.[1,6] A single example of each is presented in this report (octanal and
benzaldehyde). The main focus of the deprotection of the more difficult and
demanding unsaturated aldehyde dimethylhydrazones, for which previously
reported methodology can result in the formation of significant amounts of
unwanted side products.
The deprotection of aldehyde dimethylhydrazones with 50% aqueous
glyoxylic acid affords the aldehydes in very high yield and greater than 95%
purity (Table 2). The yield of only 84% for the deprotection of 2-methyl-2-
pentenal dimethylhydrazone can be explained by loss during the removal of
solvent in vacuo. A large excess of the reagent (approx 19 equiv of glyoxylic
acide per 1 equiv of aldehyde dimethylhydrazone) is required for optimal depro-
tection. Deprotection of the dimethylhydrazone derivative of 2-methyl-2-
pentenal with 4 equiv of glyoxylic acid was only 53% complete after 1 day
and reached the 95% completion level after 5 days. Deprotection of the dimethyl-
hydrazone derivative of 2-methyl-2-pentenal with 8 equiv of glyoxylic acid was
only 67%complete after 1 day andreached the99% completionlevel after2 days.
Deprotection was verified by GC/MS and the MS of the deprotected
aldehyde dimethylhydrazone products matched that of the starting
aldehydes. Side reactions are nonexistent or minimal, even for unsatu-
rated aldehydes. The reaction time for the formation and deprotection of
aldehyde dimethylhydrazones varied with the structure of the aldehyde. The
required reaction time increased as the degree of unsaturation increased
(entry 1 compared with entry 2 and entry 2 compared with entry 3) and also
increased when an a-methyl group was present (entry 5 compared with
entry 6). These results are an improvement over the method utilizing
aqueous CuCl2 in THF,[6] which reported yields ranging from 56%–89%.
SUMMARY
Aldehyde dimethylhydrazones can be readily prepared in the presence of
anhydrous magnesium sulfate, which scavanges water and eliminates the
need for azeotropic removal of water formed during the course of the
reaction. Aqueous glyoxylic acid can be used to deprotect aldehyde dimethyl-
hydrazones in very high yield and purity. The synthetic utility of the
dimethylhydrazone protective group, for the protection of aldehydes, should
be broadened as a result of this research.
ACKNOWLEDGMENTS
I thank David Weisleder for acquisition of NMR data and Robert J. Bartelt for
helpful discussions.

1734
R. J. Petroski
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