An unprecedented rearrangement of a 1,1-diprotected hydrazine derivative. Structure revision of a catalyst-containing by-product

Article abstract of DOI:10.1016/j.tetlet.2014.10.121

Treatment of 1-Boc-1-tosyl-hydrazine with 1,1,3,3-tetramethylguanidine (TMG) gave rise to two products, one containing and the other not containing TMG. The latter was identified as 1-Boc-2-tosyl-hydrazine. This rearrangement provided useful insight into the nature of the first product that had previously been isolated and assigned an incorrect tentative structure. To rationalize the results a plausible mechanism via a common intermediate, involving TMG as a nucleophilic catalyst is proposed. A simpler procedure for the preparation of the starting material is also presented.

Full text of DOI:10.1016/j.tetlet.2014.10.121

Tetrahedron Letters 55 (2014) 7019–7022
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unprecedented rearrangement of a 1,1-diprotected hydrazine
derivative. Structure revision of a catalyst-containing by-product
a,
Ulf Ragnarsson a, , Leif Grehn , Tõnis Pehk b
⇑
a University of Uppsala, Department of Chemsitry—BMC, Box 576, SE-751 23 Uppsala, Sweden
b National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 1-Boc-1-tosyl-hydrazine with 1,1,3,3-tetramethylguanidine (TMG) gave rise to two
products, one containing and the other not containing TMG. The latter was identified as 1-Boc-2-tosyl-
hydrazine. This rearrangement provided useful insight into the nature of the first product that had pre-
viously been isolated and assigned an incorrect tentative structure. To rationalize the results a plausible
mechanism via a common intermediate, involving TMG as a nucleophilic catalyst is proposed. A simpler
procedure for the preparation of the starting material is also presented.
Received 1 September 2014
Revised 12 October 2014
Accepted 22 October 2014
Available online 28 October 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Hydrazine derivative
Nucleophilic catalysis
Rearrangement
Structure revision
Tetramethylguanidine
The stability of aromatic sulfonamides to acids and bases and
their sensitivity to reducing agents is the basis for the application
of tosyl (Ts) and related groups for the protection of amino func-
tions.1 Similarly, tert-butyl carbamates generally exhibit high base
stability, but undergo cleavage by acids, a protection strategy that
is nowadays well established in synthetic work involving amines.
tert-Butyl sulfonylcarbamates with both types of group on the same
amino function can often be made and exploited to improve the sta-
bility and selectivity further.2,3 Sulfonylhydrazines exhibit a rather
different stability profile from sulfonamides and undergo intramo-
lecular redox reactions, and this property was exploited a long time
ago for the thermal decomposition of acylbenzenesulfonylhydra-
zines in the classical McFadyen–Stevens aldehyde reaction.4
In connection with attempts to alkylate 1,2-ditosylhydrazine,
we became intrigued by its extreme sensitivity to cleavage by a
base to form a sulfinate and nitrogen. In some experiments the
evolution of the latter became so intense that it could be observed
with the naked eye.5 Monitoring the formation of the sulfinate by
1H NMR spectroscopy, we demonstrated that with 1,1,3,3-tetra-
methylguanidine (TMG) as the base in DMSO, the reaction took
place with a half-life below two minutes. Nevertheless, Fukuyama
and co-workers. recently succeeded in preventing the decomposi-
tion of the substance and in trapping the nitrogen with bromoace-
tates to form diazoacetates.6 In our previous paper, we also studied
the reaction of a few monotosyl hydrazine derivatives with TMG,
and with Ts(Boc)NNH2 we isolated a novel TMG-containing prod-
uct that was assigned a tentative structure.5 More recent work in
our laboratory has resulted in the discovery that Ts(Boc)NNH2
can undergo an unprecedented rearrangement, and as a conse-
quence of this, to the revision of the previously described structure.
In the present Letter additional experiments are reported with the
objective to shed light on this unusual reaction.
A short summary of relevant previous results
For comparison with 1,2-ditosylhydrazine, sulfinate formation
in the presence of TMG (1.25 equiv) of four monotosylated hydra-
zine derivatives, Ts-NHNH2 (1), Ts-NHNH-Boc (2), Ts-NHNH-Z (3),
and the above-mentioned Ts(Boc)NNH2 (4), was monitored by 1H
NMR spectroscopy in DMSO-d6 at room temperature. Compounds
1–3 were selectively cleaved, although with half-lives of a few days
for 1 and several months for 2 and 3. Part of the sulfinate was
thereby converted into a sulfonate.7,8 Compound 4 behaved differ-
ently from the others and there was an obvious mismatch between
its disappearance and the slow formation of a sulfinate.
Based on two NMR experiments with 4, one of which was mon-
itored over several weeks and the other more frequently up to two
weeks, we noticed that it had reacted completely within about two
days, essentially with formation of two products in addition to the
sulfinate/sulfonate. Although our interest was initially focused on
the stability of the tosyl group, in particular the appearance of a
prominent singlet at 2.55 ppm aroused our interest, and in a
⇑
Corresponding author. Tel.: +46 18 301 116.
E-mail address: ulfragnarsson@bahnhof.se (U. Ragnarsson).
1946–2014.
http://dx.doi.org/10.1016/j.tetlet.2014.10.121
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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U. Ragnarsson et al. / Tetrahedron Letters 55 (2014) 7019–7022
small-scale preparative experiment, a solid hydrazine derivative
containing TMG, C13H21N5O3S, was isolated in modest yield. This
seemed to be the major and most interesting product, whereas
the other was obtained in a minor amount as an impure viscous
oil and was not characterized. The solid was assigned the tentative
structure, Ts-N(NH2)-CO-NC(NMe2)2, with a tetramethylguanidin-
ocarbamoyl group attached to the tosyl nitrogen, referred to as
the catalyst-containing by-product in the title of this Letter.
(2.41–2.28 ppm) the signal belonging to 4 at 2.41 ppm was the
largest, indicating that about 42% still remained, whereas those
of 5 at 2.35 ppm amounted to 33% and 2 at 2.32 ppm to 22% and
sulfinate/sulfonate to less than 4%. The prominent singlet at
2.55 ppm mentioned earlier integrates for 4 times the number of
protons compared to those at 2.35 ppm. Among the three major
sets of aromatic doublets, that belonging to 4 at 7.81/7.43 ppm also
corresponds to 42% and those of 5 at 7.68/7.29 ppm to 34% and 2 at
7.60/7.21 ppm to 20%. The latter signals were significantly broad-
ened. Similarly, the remaining strong singlets at 1.30 and
1.12 ppm correspond to about 43% and 42%, respectively, of the
total number of tert-butyl protons present, whereas the very broad
signal at 1.22 ppm integrates for about 15%.
A comparison with the spectral data for pure 5 and 2 reveals
upfield changes in the shifts of the Ts-3,5-protons at 0.03 and
0.15 ppm, respectively, in the presence of TMG. Of the Ts-Me
signals, only that of 2 undergoes a 0.05 ppm shift, also upfield.
Together with the observed broad signals, this indicates that 2
interacts strongly with TMG in DMSO.
Surprisingly, inspecting the spectrum of the same sample after
50 h demonstrated that all the signals originating from 4 were
completely missing. Moreover, the 2.35/2.32 signal ratio had
increased from 1.5 to about 2.6. Further monitoring of the reaction
gave rise to a similar spectrum after 74 h, although the amount of
sulfinate/sulfonate formed was estimated to be about 8%; both
spectra are reproduced in the Supplementary material. Another
spectrum from a different experiment after 22.5 h resulted in
figures similar to those presented in the preceding paragraph. In
this case 54% of 4 still remained.
A missing link and small scale preparative experiments
We have now studied further the unusual reactivity of 4 in the
presence of TMG. To start with we carried out an experiment with
1.25 equiv of TMG on a 5 mmol scale as described in the Supple-
mentary material, and obtained a correspondingly larger amount
of the TMG-containing material 5, as a completely stable, crystal-
line solid with all the spectral characteristics in agreement with
those given earlier.5 However, from the mother liquor, it was pos-
sible to isolate another pure solid that was identified as Ts-NHNH-
Boc9 (2), indicating that a rearrangement of the starting material
had taken place under the influence of the strong base. This obser-
vation provided a link to the nature of the first product that was
previously missing. In this Letter its structure has been revised
(compound 5 in Scheme 2).
The outcomes of varying the reaction time and temperature and
the amount of TMG used were studied, first in DMSO and then in
DMF, as detailed in Table 1. In both solvents at room temperature
the two products were formed, but in varying relative proportions.
In all cases the TMG-containing species was found to be the major
product, particularly so in entries 5 and 7. These experiments and
that at 50 °C indicated that the product ratio was strongly temper-
ature dependent. A small excess of TMG was required for complete
conversion of the substrate in DMSO within 2–3 days, but further
amounts seemed to have a negative effect on the total yield, sug-
gesting that a side-reaction had taken place. This could be due to
the increased formation of the sulfinate/sulfonate. However, these
experiments did not provide conditions for a clean rearrangement
of compound 4 into 2.
Studies on compounds 2 and 5
Authentic compound 2 in the presence of a small excess
(1.25 equiv) of TMG in DMSO is rather stable5 and exhibits the
spectral characteristics found in mixtures with 5 in the preceding
section, such as the strong upfield shift of its Ts-Me and very broad
Boc-Me signals. As compound 2 in this solvent has a pKa of 14.510
compared to 13.2 for TMGH+,11 this is obviously due to partial
deprotonation. Initial sulfinate/sulfonate formation is about
Spectral studies
1%/day, which in reactions involving 2 should progressively
increase the protonation of TMG and lead to reduced upfield shifts.
Authentic compound 5 was also studied under the same condi-
tions and was found to give rise to sulfinate/sulfonate formation at
an initial rate about 10 times faster than 2. This value is higher
than that found in connection with the monitored reaction of 4
discussed above.
Studies on compound 4
Figure
1
presents the proton spectrum of compound
4
(100 mol) after the reaction with TMG (125
l
l
mol) in 0.6 mL
of DMSO for 30 h at room temperature. In the Ts-Me region
Table 1
Small scale experiments with compound 4 and TMG
Entry
TMG (equiv)
Time (d)
Solvent
Yielda (mg)
Ratio 5/2b
Commentsc
1
2
1
2
3
3
2
1
3
3
5
6
3
7
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMF
DMF
DMF
DMF
134d
141
940
1.62
1.85
2.12
3.32
1.43
7.70
0.99
>10
RT
RT
1.25
1.25
2
0.5
1.25
1.25
1.25
1.25
2
Prepe
5 mmol, RT
RT
50 °C
RT
50 °C
4 °C
–18 °C
RT
3
4
5
6
7
8
9
10
100
121f
107
107g
93
>95% of 4
69
68
n.d.
2.74
2.13
2
DMF
RT
a
b
c
d
e
f
Yield of crude solid material.
Proton signal ratio at 2.36/2.375 ppm in DMSO-d6.
Syntheses generally performed on a 0.5 mmol scale.
Contained 19% of starting material 4.
Preparative experiment, described in Supplementary material.
Contained 47% of starting material 4.
g
Contained DMF.

U. Ragnarsson et al. / Tetrahedron Letters 55 (2014) 7019–7022
7021
Figure 1. Proton spectrum (400 MHz) of compound 4 (28.6 mg, 0.1 mmol) after reaction with TMG (1.25 equiv) in DMSO-d6 (0.6 mL) for 30 h at RT.
The revised structure of the TMG-containing product
Postulated mechanism for the rearrangement of 4 into 2 in the
presence of TMG as well as for the formation of 5
The fact that compound 4 in the presence of TMG partly rear-
ranges into 2 encouraged us to reconsider the structure of our pre-
viously isolated TMG-containing product 5, since the two
compounds are apparently formed competitively. The presence of
two unequal low field protons in 5, as in 2, together with intact
TMG and tosyl moieties, the 13C NMR spectral data, and the previ-
ously presented HRMS spectrum5 confirm the structure of this
compound as 2-[(10,10,30,30-tetramethylguanidino)-carbamoyl]-1-
tosylhydrazine instead of the 1-[(10,10,30,30-tetramethylguanidi-
no)-carbamoyl] structure tentatively given.
Compound 4 with two electron-withdrawing groups on the
same nitrogen obviously exhibits low electron density at this site,
which should affect its overall basicity dramatically. In DMSO it
even behaves as a weak acid with a pKa of 15.9,10 and with a value
for TMGH+ nearly three orders of magnitude lower it can therefore
be expected to be only marginally sensitive to deprotonation by
TMG. In contrast to 2, it does not exhibit significant changes in
its chemical shifts in the presence of this base. An analogous com-
pound was characterized as a nonbasic amine maintaining its
nucleophilicity.13
Our spectral studies of the reaction of compound 4 with TMG
established that most of the tert-butyl groups originally present
in the Boc-functions were converted into tert-butanol as judged
from the signal at 1.12 ppm.15 This indicates that 4 underwent
major CO–OtBu bond cleavage in connection with its rearrange-
ment, that we propose is initiated by nucleophilic attack of the cat-
alyst at the sulfonylcarbamate carbonyl center with formation of a
more reactive tetrahedral pre-transition state complex. Direct
deprotonation is believed to be insignificant in this case and
requires a stronger Brønsted base than TMG. This complex is then
postulated to undergo an intramolecular nucleophilic N1 to N2 shift
via a corresponding tetrahedral transition state that can lead to the
two products 2 and 5 by elimination of either TMG or butoxide. As
demonstrated in Table 1, the outcome of the final step is obviously
strongly dependent on the reaction temperature and solvents and
less so on stoichiometry and reaction time, although occasionally is
somewhat blurred by accompanying tosyl cleavage. In this context
attention should be given to the pioneering work by Namba et al.
Synthesis of Ts(Boc)NNH2 directly from 1
Originally, compound 4 was prepared from Z-NHNH2 in three
simple steps in an overall yield of 79% as described in Scheme 1.12
More recently, Namba et al. demonstrated that an N1-acyl-N1-Ts-
hydrazine derivative could be prepared with high selectivity
directly from Ts-NHNH2 with various acylating reagents and cata-
lytic amounts of 4-aminopyridine or DMAP in the presence of an
excess of triethylamine.13 Considering the fact that 4 can be crys-
tallized easily from cold ether, we decided to use Namba’s reaction
conditions with Boc2O instead. The result turned out to be highly
satisfactory and small amounts of by-products could be removed
this way. That the sulfonamide function of Ts-NHNH2 in the pres-
ence of DMAP reacts with Boc2O in preference over the N-NH2
group is a further illustration of the observation by Bordwell and
co-workers that the reaction rate increases with the acidity of
the substrate.14 The requirement for
a base (triethylamine)
strongly indicates that sulfonamide anion acts as the nucleophile.
dealing with bromohydrazidation of b,c-unsaturated N-acyl-N-tos-
ylhydrazines,16 in which the terminal amino group also reacts as a
nucleophile intramolecularly similar to that which we postulate in
the rearrangement of compound 4.
Scheme 2 highlights the role of TMG as a catalyst in the
intramolecular transfer of the Boc-group from the substrate to
Scheme 1. Original synthesis of Ts(Boc)NNH2.

7022
U. Ragnarsson et al. / Tetrahedron Letters 55 (2014) 7019–7022
Scheme 2. Postulated rearrangement and substitution mechanism.
Table 2
Experimental
Direct synthesis of Ts(Boc)NNH2 with Boc2O and DMAP from Ts-NHNH2 in the
presence of Et3N
See Supplementary material.
Entry
Reagent ratioa
Temp (°C)
Yield (%)
Acknowledgments
1
2
3
1:1.05:1.5:0.1
1:1.05:1.5:0.05
1:1.05:1.2:0.05
2
2
RT
75
71
70 + 10b
U.R. and L.G. gratefully acknowledge access to library facilities
at the University of Uppsala as well as a gift of solvent from
Medicago AB, Uppsala. T.P. acknowledges support from the
Estonian Ministry of Education and Research (grants ETF 8880
and IUT 23-7).
a
Ts-NHNH2/Boc2O/Et3N/DMAP molar ratio; all syntheses performed on
10 mmol scale.
a
b
Recovered from the mother liquor, see Supplementary material.
the product 2. Its action as a nucleophile is understood to favor
energetically nucleophilic attack by the substrate amino function
leading to the rearrangement. Competing elimination of tert-
butoxide at the transition state then results in the irreversible for-
mation of compound 5 as a by-product. Previous work (experiment
2 of Table 25) allows us to conclude that compound 2 cannot be
converted into 5 with TMG. We have also verified that in the pres-
ence of tert-butanol the reverse reaction does not take place.
Supplementary material
Supplementary data (two proton spectra related to Figure 1 and
synthetic details related to Tables 1 and 2 and compounds 2, 4 and
5) associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.10.121.
References and notes
1. Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis, 5th ed.; Wiley:
Hoboken, 2014. Chapter 7.
Retrospective considerations and conclusions
2. Henry, J. R.; Marcin, L. C.; McIntosh, M. C.; Scola, P. M.; Harris, G. D., Jr.;
Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
3. Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 1017.
4. Mosettig, E. Org. React. 1954, 8, 232.
5. Ragnarsson, U.; Grehn, L. Tetrahedron Lett. 2012, 53, 1045.
6. Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2007, 9, 3195.
7. Kaupang, Å.; Görbitz, C. H.; Bonge-Hansen, T. Acta Cryst. 2013, C69, 778.
8. Vilas, M.; Tojo, E. Tetrahedron Lett. 2010, 51, 4125.
9. Ragnarsson, U.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S. J. Chem. Res. (S) 2000, 6;
J. Chem. Res. 2000, 129.
Alkylation of hydrazine derivatives is not always straightfor-
ward and can provide surprises.17 In the initially mentioned unsuc-
cessful experiment with Ts-NHNH-Ts, its strong inherent reduction
ability in the presence of the base gave rise to exceptional tosyl
cleavage. The extension of this work to include other substrates
such as compound 4 and other bases like the superbase TMG led
to the isolation of the TMG-containing product. It became some-
thing of a marker in the present work that resulted in the discovery
of a novel rearrangement, in which TMG played the role of a cata-
lyst. From a formal point of view this is an acyl transfer reaction.
The extended work reported above has shed light on the reac-
tion leading to the anticipated TMG-containing product. Its struc-
10. Ragnarsson, U.; Grehn, L.; Koppel, J.; Loog, O.; Tšubrik, O.; Bredikhin, A.;
Mäeorg, U.; Koppel, I. J. Org. Chem. 2005, 70, 5916.
11. Kolthoff, I. M.; Chantooni, M. K., Jr.; Bhowmik, S. J. Am. Chem. Soc. 1968, 90, 23.
12. Grehn, L.; Ragnarsson, U. Tetrahedron 1999, 55, 4848.
13. Namba, K.; Shoji, I.; Nishizawa, M.; Tanino, K. Org. Lett. 2009, 11, 4970.
14. Hansen, M. M.; Harksen, A. R.; Coffey, D. S.; Bordwell, F. G.; Zhao, Y. Tetrahedron
Lett. 1995, 36, 8949.
15. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512.
16. Namba, K.; Shobo, Y.; Fujimoto, K.; Shoji, I.; Yoshida, M.; Tanino, K. Eur. J. Org.
Chem. 2014, 5196.
ture has been revised and
a plausible mechanism for its
formation is presented, linked to another rearranged product. We
therefore conclude that the objective of the project has been met.
Besides, a simpler method for the preparation of substrate 4 has
been presented.
17. Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205.