Ambient temperature zincation of N-Boc pyrrolidine and its solvent dependency

Article abstract of DOI:10.1039/c2cc31793a

Sodium TMP-zincate, [(TMEDA)Na(TMP)(^tBu)Zn(^tBu)], can deproto-zincate N-Boc pyrrolidine at ambient temperature in hexane solution, whereas in toluene the captured α-carbanion of the heterocycle attacks the solvent setting off a cascade of reactions that ultimately produce a pyrrolidine-substituted enolate.

Full text of DOI:10.1039/c2cc31793a

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COMMUNICATION
Ambient temperature zincation of N-Boc pyrrolidine and its solvent
dependencyw
Jennifer A. Garden, Alan R. Kennedy, Robert E. Mulvey* and Stuart D. Robertson
Received 10th March 2012, Accepted 4th April 2012
DOI: 10.1039/c2cc31793a
Sodium TMP-zincate, [(TMEDA)Na(TMP)(tBu)Zn(tBu)], can
deproto-zincate N-Boc pyrrolidine at ambient temperature in
hexane solution, whereas in toluene the captured a-carbanion
of the heterocycle attacks the solvent setting off a cascade of
reactions that ultimately produce a pyrrolidine-substituted enolate.
and [b-Zn(I)C4H7N-Boc] but gives no characterisational
details.
In this paper we report a new ‘‘low polarity’’ metallation
methodology for the unprecedented room temperature deproto-
nation of N-Boc pyrrolidine and, also for the first time,
provide detailed crystallographic and spectroscopic data on
a metallated N-Boc pyrrolidine intermediate.8 Investigating
the solvent dependency of this reaction, we also reveal explicit
information about the destiny of the Boc protecting group
when a metallated N-Boc pyrrolidine attacks the solvent.
Agami and Couty remarked upon the paucity of knowledge
of such metal-mediated Boc decomposition processes in a
review article.9
Pyrrolidines are an important class of nitrogen heterocycle
which feature in many natural products and pharmaceutical
agents. Treatments containing a-aryl-substituted pyrrolidines
are known for many diseases including cancer,1 Parkinson’s
disease,2 and Alzheimer’s disease.3 These heterocycles also
play various roles in catalysis.4 Functionalisation at the
a-sp3 carbon atom of the saturated, five-membered (NC4) ring
is often a key step in the synthesis of substituted pyrrolidines
and this is usually done with prior protection of the nucleo-
philic N atom, often with the bulky t-butoxycarbonyl (Boc)
group. Lithiation (C-H to C-Li exchange) can open the door
to such functionalisation provided a sub-ambient temperature
regime is strictly followed to avoid the decomposition of the
sensitive ester-carrying pyrrolidine. For example, to use sBuLi
activated by TMEDA (N, N, N0, N0-tetramethylethylenediamine)
in Et2O solution, the temperature must be lowered to ꢀ78 1C,5
while even in the absence of TMEDA the temperature can
only be raised to ꢀ30 1C (in THF solution).6 Introduction of a
chiral amine provides access to asymmetric N-Boc pyrrolidines as
pioneered by Beak through a sBuLi/(ꢀ)-sparteine combination.7
Building on this foundation, Campos and O’Brien6 have developed
an enantioselective deprotonative-lithiation/transmetallation/
Negishi coupling tandem sequence to produce a series of Boc-
protected a-arylated pyrrolidines. Post lithiation [at ꢀ78 1C in
tert-butyl methyl ether or Et2O], transmetallation via ZnCl2
generates an a-zincated pyrrolidine intermediate. However,
this is not isolated and so its exact composition and structure is
unknown. Similarly, a recent patent1 detailing the synthesis of
anti-cancer treatments which act as benzoxepin PI3K inhibi-
tors, mentions zincated pyrrolidines [a-Zn(Cl)C4H7N-Boc]
Our goal was to prepare a zincated N-Boc pyrrolidine
through a room temperature direct (single step) hydrogen-zinc
exchange reaction as a marked improvement on the low
temperature two step lithiation/ZnCl2-transmetallation protocol
generally utilised for access to organozinc compounds. Alkylzinc
reagents are weak bases incapable of executing C–H deproto-
nation on relatively non-acidic substrates (for completeness
we checked and confirmed the failure of the reaction between
t
N-Boc pyrrolidine and Bu2Zn in the presence of TMEDA)
so we turned our attention to the heteroleptic alkyl-amido
sodium zincate base [(TMEDA)Na(TMP)(tBu)Zn(tBu)], 1
(TMP = 2, 2, 6, 6-tetramethylpiperidide).10–13 One of a new
generation of reactivity-enhanced zincating reagents that work
through co-operative effects (at the simplest level via anionic
‘‘ate’’ activation) between their various components, 1 has
previously succeeded in zincating a wide variety of organic
substrates. Most relevant to this study, this includes THF,
the saturated, 5-membered O-heterocycle isoelectronic to
pyrrolidine.14 The salient feature of this precedent was not
that THF could be deprotonated, but rather that its deproto-
nation could be achieved without any decomposition (ring
opening) of the hypersensitive a-anion of THF.15 The reaction
between the cyclic amine and 1 (Scheme 1) was first performed
in hexane solution. Though this reaction was carried out at
room temperature (the reagents were stirred together for 15 min),
in order to grow X-ray quality crystals of the product the
reaction solution was cooled to ꢀ70 1C. Obtained in an isolated
yield of 65% (the filtrate NMR spectrum was convoluted but no
further product resonances were observed), these crystals were
identified as the heterotrileptic alkyl-amido-pyrrolidide complex
[(TMEDA)Na(TMP)(a-C4H7NBoc)Zn(tBu)], 2. Formally, 1 has
WestCHEM, Department of Pure and Applied Chemistry,
University of Strathclyde, Glasgow, G1 1XL, UK.
E-mail: r.e.mulvey@strath.ac.uk
w Electronic supplementary information (ESI) available: NMR spectro-
scopic data, electrophilic quench data. CCDC 871020 and 871021. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc31793a
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Chem. Commun., 2012, 48, 5265–5267 5265

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Scheme 1 Synthesis of sodium pyrrolidino-zincate 2.
Scheme 2 Postulated mechanism for the surprising generation of
enolate 3.
The surprising product obtained was the crystalline sodium
enolate [{(TMEDA)Na[OC(NC4H8)CHPh]}2], 3 (isolated yield,
18%; NMR spectroscopic analysis of the filtrate revealed no
more of this product in solutiony). Thus the participation of
toluene results at least in part in cleavage of the Boc ‘‘protecting
group’’ through elimination of the alkoxide leaving group
tBuOꢀ. The formation of 3 implies that N-Boc pyrrolidine,
having initially reacted as a Brønsted acid by surrendering a
proton to 1, can then, in its a-carbanionic form, function as a
Brønsted base by recapturing a proton from toluene. Evidence
1
that pyrrolidide deprotonates toluene comes through H NMR
monitoring of the reaction of 1 with N-Boc pyrrolidine in the
presence of deuterated toluene. Carried out in d8-THF
solution, the 1H NMR spectrum shows that the a : b ratio
decreases to 3 : 4, consistent with a mono-deuterated NC4H7D
derivative. Thus a mechanism can be postulated for the
reaction between 2 and toluene (Scheme 2).
Fig. 1 Molecular structure of 2 with thermal ellipsoids drawn at the
50% probability level and hydrogen atoms omitted for clarity. Selected
distances (A) and angles (1): Na1-O1, 2.3063(16); Na1-N2, 2.4865(17);
Na1-N3, 2.568(2); Na1-N4, 2.4498(17); Zn1-N4, 2.0354(17); Zn1-O1,
2.7959(14); Zn1-C1, 2.051(2); Zn1-C8, 2.086(2); Na1-N4-Zn1, 84.12(6);
O1-Na1-N2, 104.92(6); O1-Na1-N3, 105.70(6); O1-Na1-N4, 99.15(6);
N2-Na1-N3, 74.25(6); N2-Na1-N4, 140.19(7); N3-Na1-N4, 128.56(6);
C1-Zn1-N4, 130.81(8); C1-Zn1-C8, 117.24(9); N4-Zn-C8, 111.87(7).
Firstly the a-carbanion of the heterocycle deprotonates
toluene laterally to regenerate N-Boc pyrrolidine and to
generate a benzyl group. Secondly the benzyl nucleophile
attacks the carbonyl of the carbamate to form a carboxamide
with concomitant elimination of a t-butoxide group. Note that
the amide (benzoyl pyrrolidine), PhCH2C(QO)NC4H8, is a
known compound for which deprotonation at the PhCH2
position has been observed.19 Given the propensity of reac-
tions of 1 and similar ate reagents in non-polar solvents to
involve both metals in intramolecular processes, these events
probably occur through the putative intermediates 4 and 5
though alternative processes involving single metal complexes
cannot be ruled out. The final step is likely to involve
fragmentation of the bimetallic complex with elimination of
the zinc component ZnRR0 (R = OtBu and R0 = TMP or
tBu) accompanied by deprotonation of the PhCH2 via tBuꢀ to
generate the sodium enolate 3 (and subsequently benzoyl
pyrrolidine after an aqueous work up) and BuH or TMP(H).
Since this PhCH2 deprotonation leads to the formation of a
resonance delocalised Cꢀ ꢀ ꢀCꢀ ꢀ ꢀOꢀ unit, toluene has
effectively been doubly deprotonated in the lateral position.
Note that in the absence of the pyrrolidine, reaction between
zincate reagent 1 and toluene affords a statistical mixture of
meta- and para-tolyl isomers with no benzyl formation, thus
ruling out the participation of this reaction in that producing 3
unless some complicated rearrangement is in operation.20
Metal enolate compounds21 can be thought of as possible
been transformed into 2 by substitution of a t-butyl ligand by
an N-Boc pyrrolidine ligand deprotonated at an a-C atom.
X-ray crystallographic studies of 2 (Fig. 1)z reveal the
structural consequences of this transformation with retention
of the (TMEDA)Na(m-TMP)Zn(tBu) framework but replace-
ment of the bridging t-butyl ligand by a N-Boc pyrrolidide
bridge that connects both metal atoms through a-C-Zn
and (carbonyl)O-Na bonds leading to a 7-atom, 5-element
(NaNZnCNCO) ring.
This dual metal–ligand bonding combined with the marked
covalency of the a–C–Zn bond are presumably key factors in
stabilising the electron-rich, anionic modification of the cyclic
amine. Significantly, in contrast to the aforementioned meta-
stable lithiated forms of N-Boc pyrrolidine, crystals of this
zincated variant are stable for at least four months under an
argon atmosphere. Preliminary electrophilic quenching studies
of 2 appear promising (see ESIw). Though the synthesis of, for
example, lithium,16 zinc,1 and tin17 complexes of substituent-
free N-Boc pyrrolidine have been reported previously, a search
of the Cambridge Structural Database revealed no hits for any
metallated N-Boc pyrrolidine structure, making the structure
of 2 unique.18
Attempts to reproduce the zincation reaction in a mixed
hexane/toluene solution resulted in a different outcome.
c
5266 Chem. Commun., 2012, 48, 5265–5267
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Crystal data for 2, C28H59N4Na1O2Zn1, Mr = 572.15, orthorhombic,
space group Pbca, a = 16.8528(6), b = 19.2437(5), c = 20.3447(5) A,
V = 6598.0(3) A3, Z = 8, m = 0.785 mmꢀ1; 26 669 reflections, 7941
unique, Rint 0.0568, final refinement to full-matrix least squares on
F2 gave R = 0.0425 (F, 5320 obs. data only) and Rw = 0.0949
(F2, all data), GOF = 1.026. Crystal data for 3, C36H60N6Na2O2,
%
Mr = 654.88, triclinic, space group P1, a = 8.541(3), b = 11.032(3),
c = 11.358(3) A, a = 69.33(3)1, b = 76.16(3)1, g = 72.49(3)1, V =
944.2(5) A3, Z = 1, m = 0.092 mmꢀ1; 4600 reflections, 3341 unique,
Rint 0.0476, final refinement to full-matrix least squares on F2 gave
R = 0.0591 (F, 2312 obs. data only) and Rw = 0.1954 (F2, all data),
GOF = 1.071.
y
mixture of products. Although the yield of 3 was low (18%), the
experiment was repeated and found to be reproducible.
1H NMR spectroscopic analysis of the filtrate revealed a complex
1 PCT Int. Appl., ed. N. Blaquiere, S. Do, D. Dudley, A. J. Folkes,
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Fig. 2 Molecular structure of 3 with thermal ellipsoids drawn at the
50% probability level and hydrogen atoms omitted for clarity. Selected
bond lengths (A) and angles (1): Na1-O1, 2.359(2); Na1-O10, 2.192(2);
Na1-N1, 2.504(2); Na1-N2, 2.499(3); O1-C14, 1.282(3); C14-C15,
1.392(3); C14-N3, 1.382(4); O1-Na1-O10, 84.35(8); O1-Na1-N2,
109.88(9); O1-Na1-N1, 149.02(9); O10-Na1-N1, 124.17(9); O10-Na1-N2,
109.34(9); N1-Na-N2, 74.43(9); Na1-O1-Na10, 95.65(8); C14-O1-Na1,
97.67(15); C14-O1-Na10, 165.02(17), O1-C14-C15, 124.8(3); O1-C14-N3,
116.1(2).
intermediates in Aldol reactions so their structures attract
considerable interest though examples with amino function-
alities are relatively rare. Therefore we crystallographically
characterised 3, revealing a centrosymmetric dimeric structure
(Fig. 2) with a strictly planar (NaO)2 ring. Of length 1.392(3) A,
the C(14)QC(15) bond lies towards the longest of such bonds in
known alkali metal enolate structures, while the C(14)–O(1)
bond is concomitantly short at 1.282(3) A, suggesting a
resonance delocalised Cꢀ ꢀ ꢀCꢀ ꢀ ꢀOꢀ pattern. Ruling
out the possibility that 3 requires a mixed-metal system for
its preparation, we prepared it rationally via a 1 : 1 : 1 mixture of
benzylsodium, N-Boc pyrrolidine, and TMEDA in a hexane/
toluene medium (see ESIw).
12 J. A. Garden, A. R. Kennedy, R. E. Mulvey and S. D. Robertson,
Dalton Trans., 2011, 40, 11945–11954.
In conclusion, the temperature threshold at which metalla-
tion of N-Boc pyrrolidine can occur without decomposition
has been raised substantially by using a sodium TMP-zincate
base. However, the reaction is solvent dependent, working well
in hexane, but failing in toluene due to the Brønsted basicity of
the a-carbanion of the heterocycle, which sets off a cascade
of reactions leading ultimately to a pyrrolidine-substituted
enolate.
13 E. Hevia, A. R. Kennedy and M. D. McCall, Dalton Trans., 2012,
41, 98–103.
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L. Russo, Nat. Chem., 2010, 2, 588–591.
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We gratefully acknowledge the EPSRC (award no. EP/
F063733/1), the Royal Society (Wolfson research merit award
to R.E.M.) and George Fraser (studentship to J.A.G.) for
generous financial support.
18 Search performed 10/01/12, Version 1.14, F. H. Allen, Acta
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20 If this alternative pathway was in operation reaction of 1 with
toluene would produce 4 or a di-t-butyl isomer of 4, where 1
has reacted as a t-butyl or TMP base. See D. R. Armstrong,
J. Garcıa-Alvarez, D. V. Graham, G. W. Honeyman, E. Hevia,
A. R. Kennedy and R. E. Mulvey, Chem.–Eur. J., 2009, 15,
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Notes and references
z Single-crystal data were recorded at 123(2) K on Oxford Diffraction
instruments using graphite-monochromated Mo-Ka radiation (l =
0.71073 A). The structures were refined to convergence on F2 against all
independent reflections by full-matrix least-squares using the SHELXL-97
program.22 The data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
21 Patai Series: The Chemistry of Metal Enolates, ed. J. Zabicky, John
Wiley and Sons, Ltd., King’s Lynn, 2009.
22 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr.,
2008, 64, 112–122.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5265–5267 5267