The direct α-zincation of amides, phosphonates and phosphine oxides by H-Zn exchange

Article abstract of DOI:10.1039/b509190j

Stoichiometric or catalytic quantities of simple 2° amines greatly increase the rate of H-Zn exchange between ZnPh₂ and a range of relatively non-acidic substrates, allowing for the convenient and direct preparation of α-functionalized organozi

Full text of DOI:10.1039/b509190j

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The direct a-zincation of amides, phosphonates and phosphine oxides by
H–Zn exchange{
Mark L. Hlavinka, Jeffrey F. Greco and John R. Hagadorn*
Received (in Berkeley, CA, USA) 28th June 2005, Accepted 7th September 2005
First published as an Advance Article on the web 23rd September 2005
DOI: 10.1039/b509190j
Following this observation we initiated a systematic study of the
deprotonation of DEA by ZnPh2 promoted by a range of different
amines. Initial studies revealed that both 1u and 2u amines were
able to accelerate the H–Zn exchange reaction. For example,
heating a mixture of DEA, 1 equiv. t-BuNH2, and 2 equiv. ZnPh2
to 50 uC for 24 h formed the a-zincated amide in 26% yield
(Table 1, entry 1). The use of Et2NH under the same conditions
gave a yield of 47% (entry 2). In contrast, all 3u amines and
pyridines were ineffective (entries 3–5).
Stoichiometric or catalytic quantities of simple 2u amines
greatly increase the rate of H–Zn exchange between ZnPh2
and a range of relatively non-acidic substrates, allowing for
the convenient and direct preparation of a-functionalized
organozincs.
Functionalized organozincs are frequently used as C-nucleophiles
in the synthesis of complex organic molecules.1 Due to their low
basicities they tolerate a wide range of sensitive functional groups,
yet they react with many electrophiles and readily undergo
transmetalation reactions with transition-metal salts. Thus, they
are indispensable intermediates in many C–C bond-forming
reactions,2 particularly those mediated by Cu and Pd complexes.3
The preparation of functionalized organozincs is commonly
performed either by the direct insertion of activated Zn into
carbon–halogen bonds or by the transmetalation of organolithium
reagents with zinc halides.4 More recently, alkenylzinc and related
derivatives have been accessed by transmetalation of Zr- and
Pd-containing intermediates with Zn sources.5 Conspicuously, the
straightforward production of functionalized organozincs by
H–Zn exchange (i.e. deprotonation) is rarely used due to the
kinetic inertness of common organozincs (e.g. ZnEt2, ZnPh2). In
this communication, however, we report that stoichiometric or
catalytic quantities of 2u amines increase the rate of H–Zn
exchange between ZnPh2 and a range of relatively inert carbon
acids. By this method a-functionalized organozincs have been
conveniently prepared starting from simple amides, phosphonates,
and phosphine oxides. The amine-promoted H–Zn exchange
process involves the intermediacy of Zn amido species which are
competent for the deprotonation of the functionalized substrates.
The deprotonation of carbon acids is often limited by slow
kinetics.6 As a result dialkylzincs and ZnPh2 are only able to
ð1Þ
The steric profile of an amine is important in determining its
activity. Thus while Et2NH was moderately effective, the bulkier
i-Pr2NH afforded only 7% of the zincated product (entry 6). Small
cyclic amines gave the best results. For example, the use of 1 equiv.
of morpholine with 2 equiv. ZnPh2 gave 91% yield (entry 10).
Repeating the reaction with 3 equiv. ZnPh2 did not significantly
increase the yield (entry 11), but the use of 1 equiv. ZnPh2 gave a
reduced yield of 62% (entry 12). The use of substoichiometric
quantities of the amines gave low to modest yields, but with
multiple turnovers based on amine. For example, the reaction of
DEA, 0.1 equiv. pyrrolidine, and 1.1 equiv. ZnPh2 afforded the
zincated product in 40% yield (entry 15). Lastly, the use of ZnEt2
instead of ZnPh2 gave relatively poor results (entry 16).
Reformatsky amides are frequently used in addition reactions
with unsaturated substrates and in transmetalations with
transition-metal salts.15 The solutions of a-zincated amides
described in Table 1 are conveniently used in this context.
PhZn[CH2C(O)NEt2]16 was reacted with 1 equiv. PhCHO in
toluene solution for 12 h and quenched with NH4Cl(aq). The
expected addition product Et2NC(O)CH2CH(Ph)OH17 was
formed in 57% yield.18 The use of 10 equiv. PhCHO increased
the yield to 78%. Reaction of the same preparation of
PhZn[CH2C(O)NEt2] with 10 equiv. I2 afforded N,N-diethyl-1-
iodoacetamide19 in 88% yield.
7
deprotonate carbon acids that have pKa values below 29.
Reported examples have involved ketones,8 MeNO2,9 dimethyl
malonate,10 fluorene,11 and terminal alkynes.12,13 The reported
reactivity of Zn amidos has likewise been limited to acidic
substrates.14 Consistent with the aforementioned studies, we
observed no reaction between ZnR2 (R 5 Et, Ph) and N,N-
diethylacetamide (DEA, pKa 5 357) or N,N-diisopropylacetamide
(DIPA) in C6D6 solution at 75 uC over several days. To our
surprise, the addition of Et2NH to the above solutions led to the
formation of measurable quantities of a-zincated amides (eqn (1)).
Amine-promoted H–Zn exchange is potentially useful for many
substrates in addition to carboxy amides. Preliminary screening
has revealed promising results for a diverse set of functionalized
organics. Experiments with Me3PO and Me(MeO)2PO (DMMP)
are shown in Table 2. Relative to DEA, these substrates display
greater reactivity with ZnPh2–amine mixtures. For example,
Me3PO was zincated quantitatively in the presence of 1 equiv.
morpholine and 2 equiv. ZnPh2 at 50 uC over 24 h (entry 2).
Catalytic quantities of amines were also found to be very effective.
The use of only 0.1 equiv. pyrrolidine and 1.1 equiv. ZnPh2 formed
the zincated product in 99% yield (entry 4). H–Zn exchange
Department of Chemistry and Biochemistry, University of Colorado,
Boulder, Colorado, USA. E-mail: hagadorn@colorado.edu;
Fax: +1 303 492 5894; Tel: +1 303 492 5717
{ Electronic supplementary information (ESI) available: Experimental
details and characterization data. See http://dx.doi.org/10.1039/b509190j
5304 | Chem. Commun., 2005, 5304–5306
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Table 1 a-Zincation experiments of carboxyl amidesa
Entry
Amide
Amine (equiv.)
Zn source (equiv.)
Yieldb
1
2
3
4
5
6
7
8
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DEA
DIPA
t-BuNH2 (1.0)
Et2NH (1.0)
Et3N (1.0)
Pyridine (1.0)
4-(Dimethylamino) pyridine (1.0)
i-Pr2NH (1.0)
(Me3Si)2NH (1.0)
Piperidine (1.0)
Pyrrolidine (1.0)
Morpholine (1.0)
Morpholine (1.0)
Morpholine (1.0)
Morpholine (0.10)
Piperidine (0.10)
Pyrrolidine (0.10)
Morpholine (1.0)
None
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (2.0)
ZnPh2 (3.0)
ZnPh2 (1.0)
ZnPh2 (1.1)
ZnPh2 (1.1)
ZnPh2 (1.1)
ZnEt2 (2.0)
Zn[N(SiMe3)2]2 (1.0)
ZnPh2 (2.0)
b
26%
47%
0%
4%
0%
7%
0%
90%
88%
91%
93%
62%
30%
18%
40%
22%
49%c
86%
9
10
11
12
13
14
15
16
17
18
a
Morpholine (1.0)
Reaction conditions: amide (1.0 equiv.), amine, Zn source, toluene (2 mL), 50 uC, 24 h. Yields were determined from the ratio of deuterated
c
to non-deuterated substrate following quenching of the reaction mixture with 99.9% D2O. Initial concentrations of Zn[N(SiMe3)2]2 and DEA
were both 0.046 M.
Table 2 a-Zincation experiments of other substratesa
The first step of the mechanism was explored by observing the
reaction rate of ZnPh2 with various amines. Heating a mixture of
ZnPh2, 1 equiv. morpholine, and CD2Cl2 to 50 uC gave complete
conversion to PhZn(NC4H8O) and PhH within 15 min. The other
cyclic amines from Table 1 were also quickly deprotonated by
ZnPh2. Repeating the reaction with i-Pr2NH, however, gave ,5%
conversion after 20 h. Thus the hindered amines (i.e. i-Pr2NH,
(Me3Si)2NH) are ineffective promoters of H–Zn exchange because
they do not form Zn amidos at a reasonable rate. The use of ZnEt2
instead of ZnPh2 similarly results in the slow formation of a Zn
amido. Heating ZnEt2 and 1 equiv. morpholine in CD2Cl2 to 50 uC
gave ,30% conversion after 20 h.
Entry Substrateb Amine (equiv.)
Zn source (equiv.)
Yieldc
1
2
3
4
5
6
7
8
9
10
a
Me3PO
Me3PO
Me3PO
Me3PO
Me3PO
DMMP
DMMP
DMMP
DMMP
DMMP
None
ZnPh2 (2.0)
0%
100%
72%
Morpholine (1.0) ZnPh2 (2.0)
Morpholine (0.1) ZnPh2 (1.1)
Pyrollidine (0.1) ZnPh2 (1.1)
None
None
Morpholine (1.0) ZnPh2 (2.0)
Morpholine (0.1) ZnPh2 (1.1)
Piperidine (0.1)
None
99%
Zn[N(SiMe3)2]2 (1.0) 91%d
ZnPh2 (2.0)
0%
97%
51%
77%
ZnPh2 (1.1)
Zn[N(SiMe3)2]2 (1.0) 56%d
Reaction conditions: substrate (1.0 equiv.), amine, Zn source,
b
c
toluene (2 mL), 50 uC, 24 h. DMMP is Me(MeO)2PO. Yields
were determined from the ratio of deuterated to non-deuterated
substrate following quenching of the reaction mixture with 99.9%
D2O. Initial concentrations of Zn[N(SiMe3)2]2 and substrate were
both 0.046 M.
The second step of the mechanism involves the reversible
deprotonation of a carbon acid by a Zn amido. Related chemistry
has been reported for EtZnN(i-Pr)2 and EtZnNPh2, which
partially deprotonate t-BuC(O)Et (pKa $ 28) to form Zn enolate
and amine.14a Our studies indicate that Zn amidos are capable of
deprotonating less acidic substrates with pKa values up to 35. Thus
heating a toluene solution of mononuclear Zn[N(SiMe3)2]2
(0.046 M) and 1 equiv. DEA (0.046 M) to 50 uC for 22 h led to
49% zincation (entry 17, Table 1). Repeating the reaction with
Me3PO and Me(MeO)2PO gave 91 and 56% zincation, respectively
(Table 2, entries 5, 10).24 In all cases, increasing the reaction times
did not lead to significant changes in yield, thus indicating that
thermodynamic equilibrium had been reached.
d
reactions using Me(MeO)2PO gave similar results, although
slightly lower yields were obtained (entries 7–9).
A simplified20 mechanism for the H–Zn exchange is shown in
Scheme 1. First the 2u amine reacts with ZnPh2 to generate
PhZnNR2.21 Then this intermediate reacts with the substrate
(CH3FG) (where FG is a functional group) to form a-zincated
PhZn[CH2FG] and HNR2. The deprotonation of the substrate is
expected to be reversible, with a Keq22 dependent on the heterolytic
dissociation constants of the four reactants.14a,23
In conclusion, stoichiometric or catalytic quantities of simple 2u
amines increase the rate of H–Zn exchange between ZnPh2 and a
range of functionalized substrates. Key to this process is the
intermediacy of Zn amido species which are competent for the
deprotonation of functionalized carbon acids. Using this method
a-zincated derivatives of amides, phosphonates, and phosphine
oxides have been conveniently prepared for the first time without
the use of strongly basic or halogenated reactants.
Notes and references
Scheme 1 Proposed mechanism for the formation of a-functionalized
1 Organozinc Reagents in Organic Synthesis, ed. E. Erdik, CRC Press,
Boca Raton, 1996.
organozincs by amine-promoted H–Zn exchange.
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16 Formed in situ using the conditions described in entry 10 of Table 1.
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1
18 Yields were determined by H NMR relative to internal standards.
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20 The mechanism is ‘‘simplified’’ in that there are additional processes that
are likely to occur which complicate the mechanism. These include
dimerization and oligomerization processes as well as Schlenk-type
disproportionations. Also, the mechanism is most applicable to reactions
having only catalytic quantities of amine. When stoichiometric
quantities of amine are used the product could incorporate amine/
amido to form a mixed ligand cluster.
21 The ground-state structure of PhZnNR2 is likely to be dimeric (or
trimeric) with m-NR2 groups: Metal and Metalloid Amides, ed. M. F.
Lappert, P. P. Power, A. R. Sanger and R. L. Srivastava, John Wiley &
Sons, New York, 1980; PhZn[CH2C(O)NR92] is also likely to be dimeric
with m-C,O-[CH2(NR92)O] ligands related to those of the structurally
characterized Reformatsky ester {ZnBr(THF)[CH2C(O-t-Bu)O]}2,
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22 Keq 5 {[Ka(CH3C(O)NR92)][Kd(ZnNR2)]}/{[Ka(HNR2)][Kd(ZnCH2C-
(O)NR92)]}, with Kd a heterolytic dissociation constant. The dimeriza-
tion of PhZnNR2 and/or PhZn[CH2C(O)NR92] will also affect the
equilibrium.
23 H. E. Bryndza, L. K. Fong, R. A. Paciello, W. Tam and J. E. Bercaw,
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24 Attempts to study the equilibrium deprotonation of DEA by
PhZn(NC4H8O) at 50 uC were complicated by the (irreversible)
formation of significant quantities of PhH. Thus, direct observation of
the equilibrium was not possible.
15 a-Zincated (Reformatsky) amides in Pd-catalyzed couplings: (a)
T. Hama, X. Liu, D. A. Culkin and J. F. Hartwig, J. Am. Chem.
Soc., 2003, 125, 11176–11177; (b) E. Bentz, M. G. Moloney and
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