Reaction of the ambident electrophile dimethyl carbonate with the ambident nucleophile phenylhydrazine

Article abstract of DOI:10.1021/jo701818d

(Chemical Equation Presented) To explore the ambident electrophilic reactivity of dimethyl carbonate (DMC), reactions with the ambident nucleophile phenylhydrazine were investigated. When a Broensted base was used, selective carboxymethylation occurred at

Full text of DOI:10.1021/jo701818d

Reaction of the Ambident Electrophile Dimethyl
Carbonate with the Ambident Nucleophile
Phenylhydrazine
Anthony E. Rosamilia,† Fabio Arico`,† and Pietro Tundo*,†,‡
starting material, e.g., phenylacetonitrile, an anion is generated
with a Bro¨nsted base; the anion is a hard nucleophile and thus
reacts with DMC to produce the carboxymethylated arylaceto-
nitrile 2. Bearing the carboxylate group, the reactive carbon
anion is rendered a soft nucleophilic center and undergoes
methylation to produce the methyl carboxymethylated arylac-
etonitrile 3. Reaction between MeOH and 3 results in the
formation of 2-methyl-2-phenylacetonitrile (4), which does not
readily undergo methylation because the loss of the carboxym-
ethyl moiety renders the carbon a hard nucleophilic center,
which only permits the carboxymethylation to reproduce 3.
Significantly, the reaction was carried out with DMC as a
solvent/reagent; after complete conversion the selectivity for
the mono-methylated product 4 was >99%.
Consorzio InteruniVersitario Nazionale La Chimica per
l’Ambiente (INCA), 21/8 Via delle Industrie, Marghera (VE),
30175, Italy, and Dipartimento di Scienze Ambientali,
UniVersita` Ca’ Foscari Venezia, 2137 Dorsoduro (VE),
30123, Italy
tundop@uniVe.it
ReceiVed August 31, 2007
DMC has also been shown to react analogously with other
nucleophiles, such as amino compounds.4 In an effort to explore
this concept further, a more complex class of nucleophile was
sought. In particular, ambident nucleophiles were of interest due
to the appealing concept of exploring reactions of ambident
nucleophiles with ambident electrophiles.
To explore the ambident electrophilic reactivity of dimethyl
carbonate (DMC), reactions with the ambident nucleophile
phenylhydrazine were investigated. When a Bro¨nsted base
was used, selective carboxymethylation occurred at N-1, after
that several other compounds were produced selectively
utilizing various conditions. Formation of these compounds
was explained by using the Hard-Soft Acid-Base (HSAB)
theory. Catalysis by some metal salts altered the reactivity
of phenylhydrazine, which effected selective carboxymethy-
lation at N-2 of phenylhydrazine instead.
Phenylhydrazine was our first choice for an ambident
nucleophile. On face value, it is a relatively simple molecule.
It possesses two adjacent nitrogens; however, they differ in
reactivity due to the phenyl substituent at N-1. In the literature
there are some reports of alkylations and carboxyalkylations of
arylhydrazines, which show the differing reactivities of the two
nitrogens. Alkylations using alkylhalides such as benzylbromide
or methyliodide preferably occur at N-1 if the alkylhalide is
not overly bulky.5 Over alkylation, to produce the ammonium
salts, is observed if the hydrazine is not activated by a strong-
irreversible base such as sodium metal or butyl lithium.6
Reductive amination, via hydrazones, has been used to selec-
tively alkylate at N-2 using ketones or aldehydes and reductant.7
On the other hand, a few 3-arylcarbazates, or alkyl 2-arylhy-
drazinecarboxylates, have been synthesized in moderate yields
with use of chloroalkylformates or BOC-anhydride.8
Dimethyl carbonate (DMC) is a well-known nontoxic reagent
and solvent that has been used for many Green applications,
namely the substitution of toxic reagents such as methyl halides
and phosgene for the selective methylation and carboxymethy-
lation, respectively, of numerous nucleophiles.1 Both transfor-
mations are possible owing to the two nonequivalent electro-
philic centers of DMC, making it an ambident electrophile.
Selectivity toward either center can be attributed to the Hard-
Soft Acid-Base (HSAB) theory, introduced by Pearson.2 In the
context of DMC, the theory can be simply applied by suggesting
DMC will carboxymethylate (hard reaction) hard nucleophiles
or methylate (soft reaction) soft nucleophiles. It should be
pointed out that this classification is a relative assignment for
the differing reactivities of the two electrophilic centers of DMC.
A prime example that demonstrates both hard and soft
nucleophilicity in a tandem reaction, and is also relevant to this
report, is the reaction of arylacetonitriles with DMC.3 From the
(2) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539. Pearson,
R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827-1836.
(3) Tundo, P.; Selva, M.; Perosa, A.; Memoli, S. J. Org. Chem. 2002,
67, 1071-1077. Tundo, P.; Selva, M.; Bomben, A. Org. Synth. 2004, 76,
640.
(4) Tundo, P.; Bressanello, S.; Loris, A.; Sathicq, G. Pure Appl. Chem.
2005, 77, 1719-1725.
(5) Smith, P. A. S.; DeWall, G. L. J. Am. Chem. Soc. 1977, 99, 5751-
5760.
(6) Audrieth, L. F.; Weisiger, J. R.; Carter, H. E. J. Org. Chem. 1941,
6, 417-420. West, R.; Stewart, F. J. Am. Chem. Soc. 1970, 92, 853-859.
(7) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862. Goodwin, R. C.; Bailey,
J. R. J. Am. Chem. Soc. 1927, 49, 219-227.
(8) Huang, P.-K. C.; Kosower, E. M. J. Am. Chem. Soc. 1968, 90, 2354-
2362. Kisselijova, K.; Bhatia, P. A.; Brooks, C. D. W.; Basha, A.; Ratajczyk,
J. D.; Gunn, B. P.; Bouska, J. B.; Lanni, C.; Young, P. R.; Bell, R. L.;
Carter, G. W. J. Med. Chem. 1996, 39; 3938-3950. Tsˇubrik, O.; Sillard,
R.; Ma¨eorg, S.; Ma¨eorg, U. Org. Lett. 2006, 8, 43-45.
* Author to whom correspondence should be addressed.
† Consorzio Interuniversitario Nazionale La Chimica per l’Ambiente (INCA).
‡ Universita` Ca’ Foscari Venezia.
(1) Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706-716. Selva,
M.; Tundo, P. J. Org. Chem. 2006, 71, 1464-1470. Shieh, W.-C.; Dell,
S.; Bach, A.; Repic, O.; Blacklock, T. J. J. Org. Chem. 2003, 68, 1954-
1957.
10.1021/jo701818d CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/23/2008
J. Org. Chem. 2008, 73, 1559-1562
1559

SCHEME 1. Methylation of Phenylacetonitrile
SCHEME 2. Proposed Mechanistic Pathway for the
Reaction of Phenylhydrazine and DMC, Using a Bro1nsted
Base
FIGURE 1. Reaction of phenylhydrazine, 3 equiv of NaOMe, and
DMC at Reflux (90 °C).
SCHEME 3. Formation of Carbazate 9
producing compounds 6 and 9 as the major components (Figure
1 and Supporting Information).
A possible reaction pathway for these products is given in
Scheme 2. An important process in this reaction is the
methanolysis of 8 to produce 9 (Scheme 2, iv). Methanol is
produced in the reaction when either carboxymethylation or
methylation occurs. Therefore, the control of the amount of
MeOH in the reaction can be important for product selectivity.
In fact, phenylhydrazine (5) was reacted with DMC and KO-
t-Bu with the removal of methanol (5 Å molecular sieves) to
produce carbazate 8 in high selectivity (>90%) via carbazates
6 and 7. The removal of methanol from the reaction reduces
methanolyis, although some of carbazate 10 (<10%) was still
produced.
This paper reports the reactivity of the ambident nucleophile,
phenylhydrazine, toward the ambident electrophile, DMC, under
different conditions to possibly achieve selective reactions at
either or both of the nucleophilic centers and to explore the
HSAB nature of the nucleophile.
On the other hand, excess methanol was utilized to promote
the methanolysis. Optimum conditions were found when
methanol was added (with base) after the formation of com-
pounds 8 and 9 in reactions with DMC as the only initial solvent.
Selectivity higher than 90% was achieved for carbazate 9 by
using this method. In another procedure where methanol was
added at the beginning, more complex mixtures were produced.
A considerable amount of methyl 3-phenylcarbazate 11, possibly
a product of methanolysis of carbazate 7, was observed.
Methanolysis of both 7 and 8 with methanol (Schemes 3 and
2, iv) presumably occurs more favorably at the phenyl-
substituted nitrogen because there is a greater stabilization of
the hydrazine leaving group and also there is a greater release
of steric strain at this nitrogen possessing bulkier susbstituents.
Although carbazate 11 was produced in decent quantities with
both DMC and MeOH, the method would not be suitable for
the preparative synthesis of such methyl 3-arylcarbazates due
to the degree of coproduct formation. Although it was not our
main aim, we report preliminary results for the preparative
synthesis of methyl 3-phenylcarbazate (11) using classical metal
catalysts.
To effect carboxymethylation of phenylhydrazine similar
conditions to those that have been used previously for amino
nucleophiles were implemented with DMC also used as a
solvent.4 Base catalysts such as potassium tert-butoxide, sodium
methoxide, and cesium carbonate effected carboxymethylation
of the phenyl-substituted nitrogen to produce 6 (Scheme 2, i),
albeit at different rates and selectivity. The rate of the reactions
proceeded in order of base strength, i.e., KO-t-Bu > NaOMe
> Cs2CO3 > K2CO3 (no reaction). In fact, when potassium tert-
butoxide was used at room temperature selective carboxym-
ethylation (85%) was observed. It was only under these
conditions that the carbazate 6 could be selectively produced
and isolated.
When reactions were conducted at reflux (90 °C), subsequent
reactions took place. First, carboxymethylation of carbazate 6
at N-2 to produce 7 occurred (Scheme 2, ii), followed by
methylation (of 7) to produce 8 (Scheme 2, iii). Although
significant quantities of each compound could be found during
the reactions, large conversions of phenylhydrazine with great
selectivity for either product were not achieved under normal
reflux conditions. Carbazate 7 was converted into carbazate 8;
however, this was accompanied by further reactions that
produced carbazates 9 and 10. Usually, mixtures containing
mainly 8 and 9 were obtained when KO-t-Bu or NaOMe was
used; however, reactions with Cs2CO3 progressed more slowly
Pb(OAc)2 and Sn[O2CCH(Et)Bu]2 in the absence of base were
successful in producing carbazate 11 selectively with complete
conversion of the phenylhydrazine. With these catalysts activa-
tion of the primary nitrogen, N-2, rather than the secondary
anilino nitrogen, N-1, was observed. Also methylation was not
1560 J. Org. Chem., Vol. 73, No. 4, 2008

TABLE 1. Synthesis of Carboxymethylated Hydrazines from Phenylhydrazine
entry product
base/catalyst
equiv of base
conditions
time
25 min
3 h 10 min
5 h 40 min
yield (%)
comment
1
2
3
6
8
9
KO-t-Bu
KO-t-Bu
NaOMe
1
1
4
Rt
85a
95a
79a
reflux, removal of MeOH
reflux, 3 equiv of NaOMe
1 equiv of NaOMe and MeOH, reflux 3 h 30 min
>90% purityb
>95% purityb
>95% purityb
4
5
11
11
Pb(OAc)2
Pb(OAc)2
1
reflux
18 h
89b
76a
88b
70a
58a
36a
65a
0.2
reflux
20 h
6
11
11
10
Sn[O2CCH(Et)Bu]2
Ti(O-t-Bu)4
KO-t-Bu
0.2
1
5
reflux
reflux
25 h 45 min
51 h
35 h
7
80% of 11; 20% of 6b
8c
reflux, 2 equiv of base added at
0 and 3 h and 1 equiv at 32.5 h
a Isolated product. b Crude product. c Performed with 1-methyl-1-phenylhydrazine (12).
SCHEME 4. Reaction of 1-Methyl-1-phenylhydrazine with
DMC, Using a Bro1nsted Base
FIGURE 2. Acid-base equilibrium of phenylhydrazine and potassium
butoxide.
observed. When Ti(O-t-Bu)4 was used, the reaction took
considerably more time and the selectivity toward carbazate 11
over carbazate 6 was 80% after complete conversion of
phenylhydrazine (Table 1, entry 7). In either case, apparently
these metal complexes activated phenylhydrazine for attack as
a hard nucleophile, more prominently at N-2, which is different
from the activation by a Bro¨nsted base.
hydrogens,10 or/and a general basic catalysis occurs (see ref 4
for comparison).
Results from reactions with 1-methyl-1-phenylhydrazine (12)
(Table 1, entry 8 and Scheme 4) demonstrate the importance
of the substituents at N-1. In this case an electron-donating
substituent is present, which results in the deactivation of N-2
of the hydrazine in this reaction, presumably increasing the pKa
of N-2. Only when KO-t-Bu, the stronger base, was used was
significant conversion of 1-methyl-1-phenylhydrazine (12)
observed. However, even in this case 5 equiv were required to
effect full conversion of the hydrazine because the methanol
produced from the reaction buffers the system, therefore
reducing the base strength in the reaction.
Once 7 is produced, N-2 is rendered a soft nucleophile due
to its ability to delocalise its electrons across the carbonyl
moiety. Similar to primary amines and anilines, N-2 of carbazate
7 is subsequently methylated (Scheme 2, iii) to produce 8. After
methylation, both nitrogens are fully substituted, and as
discussed before methanolysis at the N-1 occurs producing
carbazate 9.
The HSAB theory can be adequately used to interpret the
reaction when using a strong base. As observed with primary
amines and anilines,4 phenylhydrazine reacts in a similar
manner; however, in this case there is the equivalent of both a
primary and a secondary amine. When KO-t-Bu is used, there
are two likely explanations for the initial key reaction, which
produces 6 (Scheme 2, step i). Either the base weakens the N-H
bond of N-1 via coordination to the proton increasing the
nucleophilicity of N-1 or deprotonation of N-1 occurs, which
produces the phenylhydrazinide anion (Figure 2). The latter is
likely, because the pKa of phenylhydrazine (N-1), 28.8, is lower
than that of tert-butanol, 32.2.9
Therefore, the anion of phenylhydrazine, a harder nucleophile
and much more reactive than the Lewis basic NH and NH2,
attacks the hard carbon of DMC to form carbazate 6. Similar
activation of phenylhydrazine with strong bases has been utilized
previously in alkylations of phenylhydrazines with equivalent
chemoselectivity.6 In the case of NaOMe and Cs2CO3, which
are weaker bases, carboxymethylation is made possible at reflux
temperature (90 °C).
Carbazate 9, bearing an N-H, is able to react with DMC
once again. The reaction of isolated carbazate 9 with KO-t-Bu
in refluxing DMC produced both carbazate 10 (36%) and
compound 8 (46%) after 2 h, suggesting that N-1 of carbazate
9 possesses both hard and soft nucleophilic nature. The
difference in nucleophilicity from that of the same nitrogen of
phenylhydrazine is most likely due to the substitutents of N-2.
Carbazate 9 possesses a carboxymethyl group at N-2, which
can affect the electron density of N-1, similar to the effect
discussed previously. Therefore, with both an adjacent phenyl
ring and neighboring carbamate moiety, this carbazate can allow
for more stabilization of N-1 nonbonding electrons, giving the
borderline nucleophilicity.
In the following step (Scheme 2, ii), carboxymethylation
occurs at N-2. It is possible that this reaction occurs via a similar
mechanism as the previous reaction (Scheme 2, step i). For this
mechanism to occur the pKa of the N-2 would have to be
significantly lower than that at N-2 of the parent hydrazine 5.
Although the carboxymethyl moiety is not directly attached to
N-2 its presence may still assist in reducing the pKa of the N-2
In conclusion, under basic conditions phenylhydrazine, and
its products, reacted with DMC in accordance with the HSAB
theory. It was also shown that the reactivity of both nitrogens
(9) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980,
45, 3295-3299. Zhao, Y.; Bordwell, F. G.; Cheng, J.-P.; Wang, D. J. Am.
Chem. Soc. 1997, 119, 9125-9129.
(10) With some hydrazines, the pKa of N-2 is lower in comparison to
the parent hydrazine if there is an electron-withdrawing group present on
the adjacent nitrogen, ref 9.
J. Org. Chem, Vol. 73, No. 4, 2008 1561

40 min another equivalent of NaOMe (0.200 g, 3.70 mmol) and
MeOH (4.74 g, 0.148 mmol) were added and the reaction was
refluxed. After 3 h 30 min the reaction was cooled to room
temperature followed by pouring the reaction mixture on silica gel
suspended in ether and stirring at room temperature for 30 min.
After this time the reaction components were washed through the
silica gel with ether. The filtrate was evaporated and the solvent
removed in vacuo leaving an orange oil. The oil was chromato-
graphed on silica gel using a 1:1 Et2O/hexane mixture as the eluent,
which yielded the desired product 9 as an orange oil (Rf 0.20, 0.530
g, 79%). 1H NMR (300 MHz, CDCl3) δ 3.24 (s, 3H), 3.72 (s, 3H),
5.97 (br s, 1H), 6.72 (d, J ) 7.7 Hz, 2H), 6.83-6.92 (m, 1H), 7.24
(dd, J ) 8.5, 7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 37.5 (br),
53.3, 112.8, 120.8, 129.3, 147.8, 157.7. Mass spectrum (EI) m/z
180 (M+, 65%), 121 (PhNHNMe+, 85), 92 (100), 77 (Ph+, 40), 65
(45). HRMS (ESI) m/z calcd for C9H12N2O2 (M+•) 180.0893, found
180.0912.
Synthesis of Methyl 3-Phenylcarbazate (11). A stirring suspen-
sion of phenylhydrazine (0.800 g, 7.40 mmol), Pb(OAc)2 (2.41 g,
7.40 mmol), and dimethyl carbonate (26.64 g, 0.296 mol) was
heated at reflux for 18 h. After this time, Et2O (25 mL) was added
to the reaction mixture and the resulting suspension was poured
onto a silica plug, filtered, and washed with ether. The volatile
components of the filtrate were removed in vacuo to afford a light
orange solid (1.10 g, 89%, >95% purity GC). The solid was
recrystallized with boiling toluene, which yielded a white solid
(0.937 g, 76%), mp 115.5-116.0 °C (lit.8 mp 110.0-111.0 °C).
1H NMR (300 MHz, CDCl3) δ 3.77 (s, 3H), 5.77 (s, 1H), 6.56 (br
s, 1H), 6.84 (d, J ) 8.0 Hz, 2H), 6.91 (t, J ) 7.4 Hz, 1H), 7.25 (t,
J ) 7.9 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 52.9, 113.1, 121.1,
129.3, 147.9, 157.6. Mass spectrum (EI) m/z 166 (M+, 73%), 134
(PhN2H+, 26), (PhN2H2+, 100), 91 (24), 77 (Ph+, 71). HRMS (EI)
m/z calcd for C8H10N2O2 (M+•) 166.0737, found 166.0751.
is affected by the susbstituents of the other and subtle changes
to the HSAB nucleophilicity were observed. Such results show
that many compounds can be selectively produced with ambi-
dent nucleophiles under different conditions showing the
versatile nature of DMC.
Experimental Section
Synthesis of Methyl 2-phenylcarbazate (6). To a stirring
solution of phenylhydrazine (0.400 g, 3.70 mmol) and dimethyl
carbonate (13.33 g, 0.148 mol) was added KO-t-Bu (0.415 g, 3.70
mmol) and the mixture was left to react for 25 min at rt. After this
time, Et2O (40 mL) was added to the reaction mixture and the
resulting suspension was poured onto silica gel, then filtered through
a silica plug and washed with ether. The volatile components of
the filtrate were removed in vacuo to afford an orange oil, which
was crystallized with ether (0.524 g, 85%), mp 71.5 - 73.0 °C. 1H
NMR (300 MHz, CDCl3) δ 3.75 (s, 3H), 4.52 (s, 2H (disappeared
with D2O)), 7.13 (t, J ) 7.3 Hz, 1H), 7.31 (t, J ) 7.2 Hz, 2H),
7.43 (d, J ) 8.0 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 53.5,
123.7, 125.7, 128.5, 142.7, 156.8. Mass spectrum (EI) m/z 166 (M+,
75%), 107 (PhN2H2+, 100), 91 (10), 77 (Ph+, 95). HRMS (EI) m/z
calcd for C8H10N2O2 (M+•) 166.0737, found 166.0737.
Synthesis of Dimethyl 1-Phenyl-2-methylhydrazine-1,2-di-
carboxylate (8). Phenylhydrazine (0.800 g, 7.40 mmol) and DMC
(45 g, 0.50 mol) were added to an RBF equipped with a magnetic
stirrer bar and a Dean-Stark apparatus containing 5 Å molecular
sieves (leaving 14 mL solvent capacity). The reaction mixture was
stirred and heated at reflux. Once refluxing, KO-t-Bu (1.00 g, 8.91
mmol) was added to the reaction mixture which was left heating
at reflux for 3 h 10 min. After this time, the reaction was cooled to
room temperature and Et2O (25 mL) was added. The resulting
suspension was filtered though silica gel. The volatile components
of the filtrate were removed in vacuo to afford a light orange oil
1
(1.67 g, 95%). H NMR (300 MHz, DMSO, 355 K) δ 3.07 (s,
Acknowledgment. Contributions from the Consorzio Inter-
universitario Nazionale “La Chimica per l’Ambiente”, INCA
(Interuniversity National Consortium “Chemistry for the Envi-
ronment”). We also thank both Prof. V. Lucchini and Prof. S.
Antoniutti for their assistance with NMR spectroscopy.
3H), 3.64 (s, 3H), 3.68 (s, 3H), 7.15-7.20 (m, 1H), 7.28-7.35
(m, 1H). 13C NMR (300 MHz, d6-DMSO, 355 K) δ 36.5, 53.7,
53.8, 123.7, 126.6, 129.2, 140.7, 154.3, 156.6. Mass spectrum (EI)
m/z 238 (M+, 53%), 179 (PhN2MeCO2Me+, 17), 151 (PhNCO2-
Me, 70), 135 (38), 119 (20), 106 (50), 91 (30), 77 (Ph+), 59 (35),
43 (35). HRMS (EI) m/z calcd for C11H14N2O4 (M+•) 238.0948,
found 238.0915.
Supporting Information Available: Full experimental details,
spectral data, and characterization for all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
Synthesis of Methyl 2-Methyl-2-phenylcarbazate (9). To a
stirring solution of phenylhydrazine (0.400 g, 3.70 mmol) and
dimethyl carbonate (13.32 g, 0.148 mol) was added NaOMe (0.600
g, 11.10 mmol) and the suspension was heated at reflux. After 5 h
JO701818D
1562 J. Org. Chem., Vol. 73, No. 4, 2008