Evidence for the role of tetramethylethylenediamine in aqueous negishi cross-coupling: Synthesis of nonproteinogenic phenylalanine derivatives on water

Article abstract of DOI:10.1021/jo102334c

The structure of the alkylzinc-tetramethylethylenediamine (TMEDA) cluster cation 3 has been determined in the gas phase by a combination of tandem mass spectrometry, infrared multiphoton dissociation (IRMPD) spectroscopy, and DFT calculations. Both sets of experimental results establish the existence of a strongly stabilizing interaction of TMEDA with the zinc cation. High-level DFT calculations on the alkylzinc-TMEDA cluster cation 3 allowed the identification of two low energy conformers, each featuring a four-coordinate zinc atom with a bidentate TMEDA ligand, and internal coordination from the carbonyl group of the Boc group to zinc. The experimental IRMPD spectrum is reproduced with an appropriately weighted combination of the IR spectra of the two conformers identified by theory. DFT calculations on the structure of the alkylzinc halide 2 with coordinated TMEDA using the PCM model of water solvent suggest that TMEDA can promote ionization of the zinc-iodine bond in organozinc iodides under aqueous conditions, providing a credible explanation for the role of TMEDA in stabilizing the carbon-zinc bond. Reaction of the serine-derived iodide 1 with aryl iodides "on water", promoted by nano zinc in the presence of PdCl₂ (Amphos) ₂ (5 mol %) and TMEDA, leads to the formation of protected phenylalanine derivatives 4 in reasonable yields. In the case of ortho-substituted aryl iodides and aryl iodides that are solids at room temperature, conducting the reaction at 65°C gives improved results. In all cases, the product 5 of reductive dimerization of the iodide 1 is also isolated.

Full text of DOI:10.1021/jo102334c

ARTICLE
pubs.acs.org/joc
Evidence for the Role of Tetramethylethylenediamine in Aqueous
Negishi Cross-Coupling: Synthesis of Nonproteinogenic
Phenylalanine Derivatives on Water
||
Andrew J. Ross,† Frank Dreiocker,‡ Mathias Sch€afer,‡ Jos Oomens,§, Anthony J. H. M. Meijer,†
Barry T. Pickup,† and Richard F. W. Jackson*,†
†Department of Chemistry, The University of Sheffield, Dainton Building, Sheffield, S3 7HF, U.K.
‡Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 K€oln, Germany
§FOM Institute for Plasma Physics Rijnhuizen, Edisonbaan 14, Nieuwegein 3439 MN, The Netherlands
University of Amsterdam, Science Park 904, 1098XH Amsterdam, The Netherlands
S Supporting Information
b
ABSTRACT: The structure of the alkylzinc-tetramethylethyl-
enediamine (TMEDA) cluster cation 3 has been determined in
the gas phase by a combination of tandem mass spectrometry,
infrared multiphoton dissociation (IRMPD) spectroscopy, and
DFT calculations. Both sets of experimental results establish the existence of a strongly stabilizing interaction of TMEDA with the
zinc cation. High-level DFT calculations on the alkylzinc-TMEDA cluster cation 3 allowed the identification of two low energy
conformers, each featuring a four-coordinate zinc atom with a bidentate TMEDA ligand, and internal coordination from the
carbonyl group of the Boc group to zinc. The experimental IRMPD spectrum is reproduced with an appropriately weighted
combination of the IR spectra of the two conformers identified by theory. DFT calculations on the structure of the alkylzinc halide 2
with coordinated TMEDA using the PCM model of water solvent suggest that TMEDA can promote ionization of the zinc-iodine
bond in organozinc iodides under aqueous conditions, providing a credible explanation for the role of TMEDA in stabilizing the
carbon-zinc bond. Reaction of the serine-derived iodide 1 with aryl iodides “on water”, promoted by nano zinc in the presence of
PdCl2(Amphos)2 (5 mol %) and TMEDA, leads to the formation of protected phenylalanine derivatives 4 in reasonable yields. In
the case of ortho-substituted aryl iodides and aryl iodides that are solids at room temperature, conducting the reaction at 65 °C gives
improved results. In all cases, the product 5 of reductive dimerization of the iodide 1 is also isolated.
’ INTRODUCTION
cross-coupling.9 When benzylic halides were used as sub-
strates under similar conditions (although in the absence of
a surfactant), the products of cross-coupling were obtained in
an “on-water” reaction.10 Lipshutz suggested that TMEDA, a
strongly coordinating ligand, might play a role in stabilizing
the presumed alkylzinc halide intermediates in the presence of
water.10,11 It appeared to us that the mechanism of such
stabilization might involve TMEDA-induced ionization of
the zinc-halogen bond, as we had previously suggested with
DMF as ligand,8 as shown in eq 1. TMEDA adducts of
alkylzinc cations have been detected in the gas phase,4
suggesting that this process can occur.
We have recently structurally characterized a series of func-
tionalized alkylzinc cations in the gas phase1 by use of electro-
spray ionization and IRMPD spectroscopy.2,3 Related studies on
solvated alkylzinc cations4 and on organozincates5,6 using ESI
have been reported by Koszinowski, and other studies exploring
the correlation between ESI spectra of metal/ligand complexes
and their solution properties have been reviewed.7 The functio-
nalized alkylzinc cations that we studied were obtained from the
corresponding alkylzinc iodides prepared in DMF solution and
contain coordinated DMF solvent. DFT calculations have sug-
gested that coordination of DMF to alkylzinc iodides can induce
(partial) cleavage of the zinc-iodine bond to form a tight ion
pair,8 resulting in significant cationic character at zinc. An
expected consequence is that the resulting alkylzinc cation is
much less easy to protonate than a neutral alkylzinc iodide,
providing a credible explanation for the high tolerance of
alkylzinc iodides toward acidic protons. Recently, Lipshutz has
reported that treatment of simple alkyl iodides with zinc, aryl
bromides, a nonionic surfactant, a palladium catalyst, and cru-
cially TMEDA, in water, leads to the products of Negishi
Furthermore, the possibility of applying the Lipshutz condi-
tions to the alkyl iodide 1, which has been widely employed for
Received: December 1, 2010
Published: February 14, 2011
r
2011 American Chemical Society
1727
dx.doi.org/10.1021/jo102334c J. Org. Chem. 2011, 76, 1727–1734
|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Fragmentation Reactions of the Alkylzinc-
TMEDA Cluster Ion 3 at m/z 382 upon CID in an Octapolea
Figure 1. Calculated structure of cation 3 (axial methyl ester) in the gas
phase.
Figure 2. Calculated structure of cation 3 (equatorial methyl ester) in
the gas phase.
the synthesis of enantiomerically pure R-amino acids,12,13 ap-
peared to be very attractive, since it potentially opens the
possibility of applying Negishi cross-coupling to post-transla-
tional modification of peptides in the presence of water.14 The
compatibility of iodide precursor 1 with TMEDA remained to be
established, since the iodide 1 is known to be sensitive to base,
undergoing elimination to the corresponding dehydroalanine
derivative.
a The depicted ion structures are indicative and are consistent with
determined accurate ion masses.
These calculations suggested that, in vacuo, the conformer with
the axial methyl ester (Figure 1) was more stable than the
conformer with an equatorial methyl ester (Figure 2), which
was found to be 5.9 kJ mol-1 higher in energy. The calculations
were conducted with BSSE corrections,15 although the stability
order was not influenced by such corrections. It appears that the
ester carbonyl in the axial conformation can interact with the
cationic zinc center, and this evidently provides more stabiliza-
tion than the alignment of the carbamate N-H and the ester
carbonyl through minimization of the dipole.1
In order to explore the structure experimentally, the alkylzinc
iodide 2 was prepared from protected iodoalanine 1 in DMF,
TMEDA added, and the solution studied by ESI-MS in positive-
ion mode. The base peak in the ESI-MS spectrum exhibits the
fingerprint isotopic pattern of zinc (see Figure 1S in the
Supporting Information), and the ion at m/z 382 was identified
to be the signal of the TMEDA cation 3, by determination of the
exact ion mass (64Zn isotope). Due to the stability of ion 3 at m/z
382, it could easily be selected as a precursor for CID product ion
’ RESULTS AND DISCUSSION
While structure determination in solution is complex due to
solvation and conformational mobility, we have already estab-
lished that a combination of IRMPD and DFT calculations can
be used for precise structure determination of alkylzinc cations in
the gas phase.1 As a starting point, we have therefore investigated
the structure of zinc cations derived from alkylzinc iodide 2, with
coordinated TMEDA. Calculations on the free cation 3 allowed
the identification of two low energy conformers, featuring four-
coordinate zinc, with a bidentate TMEDA ligand and internal
coordination from the carbonyl group of the Boc group to zinc.
1728
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734

The Journal of Organic Chemistry
ARTICLE
Figure 4. Comparison of experimental spectra (red) for cation 3 with
the calculated spectrum resulting from a mixture of axial and equatorial
methyl esters in ratios of 91:9 (green) and 79:21 (blue).
Figure 3. Comparison of experimental and calculated spectra (axial/
equatorial) for cation 3.
experiments which exhibit a number of characteristic fragment
ions (Scheme 1). As Scheme 1 illustrates, the TMEDA ligand is
retained throughout the activation events while parts of the
organic ligand (e.g., 2-methylpropene, C4H8, and isocyanic acid
HNCO) are lost in fragmentation reactions by rearrangement
and cleavage of covalent bonds. This observation suggests the
existence of a very strong interaction of the TMEDA ligand with
the zinc ion, an interaction which apparently survives substantial
activation. However, two product ions are found in the low mass
range at m/z 70 and 115, which originate from secondary
fragmentation reactions of the TMEDA-zinc precursor ions in
the octapole CID product ion spectrum.
The TMEDA cation 3 was also sufficiently stable for IRMPD
experiments.1 Figure 3 shows the experimental spectrum, to-
gether with the theoretical spectra predicted for the axial and
equatorial isomers. For comparison to IRMPD spectra, the
experimental frequencies were scaled16,17 by 0.98.18,19 The
intensities of both theoretical spectra were scaled (by the same
amount) to obtain qualitative agreement between the theoretical
spectra and the experimental spectrum for the peaks at between
1100 and 1300 cm-1. As is clear from Figure 3, the agreement
between the spectrum for the isomer with the axial methyl ester
(Figure 1) and the experimental spectrum is almost exact. All
major peaks coincide at approximately the right intensities, apart
from the ester carbonyl stretch at 1750 cm-1, the intensity of
which was also overestimated in our earlier calculations.1 The
agreement between the spectrum for the isomer with the
equatorial methyl ester (Figure 2) and the experimental data is
less convincing. In particular, there are major discrepancies in
the region between 1600 and 1800 cm-1 as well as a missing peak
at 1300 cm-1 and a spurious one at 1075 cm-1. As a result we can
conclude with confidence that the major isomer of cation 3
observed in the experiment has the methyl ester in an axial
orientation (Figure 1). It is necessary to express the caveat that all
our calculations are done in the harmonic approximation and
assume linear absorption conditions, whereas IRMPD spectros-
copy involves a multiphoton nonlinear process in which inten-
sities and band widths are influenced in a subtle manner by the
extent of anharmonicity of the vibrations and by unpredictable
coupling of vibrational modes.20,21 However, it has been estab-
lished that relative intensities of IRMPD spectra are in fair
Figure 5. Calculated lowest energy structure for 2. TMEDA in vacuo.
agreement with those of linear absorption spectra,3,22,23 which
makes us confident of our assignment.
However, from the energy difference between isomers (5.9 kJ/
mol) it is clear that we should consider the possibility that more
than one isomer is present. To investigate this further we
simulated two additional spectra, based on mixtures of axial
and equatorial isomers. The composition of these mixtures was
taken from either the energy difference between the isomers
(leading to a 91:9 mixture in favor of the axial isomer) or the
Gibbs energy difference (3.3 kJ mol-1) between the isomers
(leading to a 79:21 mixture in favor of the axial isomer). These
spectra are plotted in Figure 4 with the experimental spectrum.
When these spectra are compared to the pure spectrum for the
axial isomer in Figure 3, it is clear that each of the simulated
spectra in Figure 4 give an agreement with the experimental
spectrum that is as good as the agreement for the axial isomer,
meaning that indeed we cannot exclude the possibility of two
isomers being present.
Having determined the structure of the cation 3 in the gas
phase, which demonstrated the effectiveness of DFT methods for
determining the structures of relevant species (at least in vacuo),
attention now turned to the more complex problem of investi-
gating the structure of the alkylzinc halide 2 with coordinated
TMEDA. Two sets of DFT calculations24 were therefore con-
ducted to determine the structure of the alkylzinc iodide 2 with
coordinated TMEDA. The first set of calculations was carried out
1729
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734

The Journal of Organic Chemistry
ARTICLE
Scheme 2. Preparation of Phenylalanine Derivatives 4 Using
Liquid Aryl Iodides
Table 1. Preparation of Phenylalanine Derivatives 4 Using
Liquid Aryl Iodides
yield (%)
Figure 6. Calculated lowest energy structure for 2 TMEDA in water
using PCM.
3
entry
Ar
C6H5
product
room temp
65 °C
1
2
4a
4a
4b
4c
4d
4e
4f
67 (66)a
35b
24
C6H5
3
C10H7
29
19
37
32
56
48
54
54
72
4
2-MeC6H4
2-FC6H4
20
5
18
6
2-ClC6H4
3-MeOC6H4
3-CF3C6H4
3-ClC6H4
3,5-F2C6H3
4-FC6H4
17
7
51
8
4g
4h
4i
47
9
44
10
11
12
13
14
39
4j
50
34b
4-FC6H4
4j
Figure 7. Calculated structure for 2 TMEDA with an axial ester in
3
4-CF3C6H4
4k
42
42
53
water using PCM.
3,4-F2C6H3
4l
51
a Using PdCl2(Amphos)2 (1 mol %). b Using the corresponding aryl
bromide.
However, when calculations were carried out using a PCM
model of water solvent, the lowest energy structure identified
now featured internal coordination of the carbamate carbonyl
group to zinc, an equatorial ester group, and ionization of the
zinc-iodine bond (Figure 6). The conformer with an axial ester
(Figure 7) was higher in energy by 3.5 kJ mol-1, and the lowest
energy covalent conformer (Figure 8) was less stable again by a
further 1.9 kJ mol-1. Notwithstanding the fact that PCM only
takes into account the interaction of a molecule with a bulk
dielectric medium and that hydrogen bonding is not included,
these results suggest that the ionization shown in eq 1 can indeed
occur under aqueous conditions and encouraged us to explore
possible synthetic applications of the alkylzinc iodide 2 under
aqueous conditions.
Phenylalanine Synthesis in Water. Initial application of the
Lipshutz “in water” conditions9 to protected iodoalanine 1 and
iodobenzene, at room temperature, in the presence of a variety of
surfactants (Tween 80, PTS and Brij 30, as 2% solutions in
water), was encouraging in that protected phenylalanine 4a was
formed, but the yields were low (6-27%) and substantial
amounts of the starting iodide 1 were isolated. Reactions carried
out in the absence of surfactant, the “on water” conditions,10 gave
a similarly low yield of 4a (16%). Although Lipshutz has reported
that the use of nano zinc with less functionalized alkyl halides
resulted in an uncontrolled reaction, and led only to protonation
of the organozinc reagent,11 use of nano zinc in place of zinc dust
with the iodide 1 gave much improved results. Optimized
reaction conditions used PdCl2(Amphos)2 (5 mol %), nano zinc
Figure 8. Calculated lowest energy covalent structure for 2 TMEDA in
water using PCM.
3
in vacuo, as this more closely resembles the situation already
studied experimentally. The second set of calculations was
conducted with a PCM model of water solvent. The latter
calculations were designed to allow an investigation of the
structure of the alkylzinc iodide 2 with coordinated TMEDA in
an aqueous environment, as a prelude to applying the Lipshutz
conditions to iodide 1. We note that these calculations were not
subjected to BSSE corrections, since they are unavailable for
PCM.
All the low energy conformations that were identified in vacuo
for the structure of the alkylzinc halide 2 with coordinated
TMEDA feature a four-coordinate zinc atom with a bidentate
TMEDA ligand and an intact zinc-iodine bond. The lowest
energy conformer identified is shown in Figure 5. The carbamate
N-H and the ester carbonyl are aligned, so as to minimize the
dipole (as we have seen before).8
1730
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734

The Journal of Organic Chemistry
ARTICLE
Table 2. Optimization of the Cross-Coupling Reaction of
1 with 4-Chloroiodobenzene
Scheme 4. Reductive Dimerization of Protected
Iodoalanine 1
entry
temp (°C)
cosolvent
time (h)
yield of 4n (%)
1
2
3
4
5
6
7
20
20
20
65
65
65
65
16
16
16
3
16
THF
43
toluene
40
36
64 (73)a
4
THF
4
37
Table 4. Reductive Dimerization of Protected Iodoalanine 1
toluene
4
42
a 2 equiv of 4-chloroiodobenzene used.
entry
solvent
temp (°C)
yield (%)
1
H2O/toluene
H2O/toluene
DMF
20
65
20
65
65
8
40
38
44
21
Scheme 3. Negishi Cross-Coupling with Solid Aryl Iodides
2
3
4
5a
DMF
DMF
a No PdCl2(Amphos)2 used.
a liquid and 4-chloroiodobenzene is a solid, mp 53-54 °C). A
series of optimization experiments was carried out to investigate
the role of temperature, cosolvent, and the influence of the
amount of aryl iodide on the efficiency of the cross-coupling
(Table 2). As is evident, better results were obtained when the
reaction was conducted at 65 °C (Table 2, entry 5), and some-
what surprisingly in the absence of added cosolvent (Table 2, cf.
entry 5 with entries 6 and 7). The optimum yield was obtained
using a 2-fold excess of the aryl iodide, resulting in a much
improved yield of the desired product 4n (73%). Attempts were
made to undertake the reaction in the absence of water, but the
melt was too viscous to stir effectively. From these results it
appears likely that the reaction is taking place on the surface of
the water (“on water”10) and that for best results the aryl iodide
needs to be liquid at the temperature at which the reaction is
conducted.
Application of the modified method to a range of solid aryl
iodides was then undertaken. For (relatively) low-melting aryl
iodides, the general method works reasonably effectively
(Scheme 3, Table 3). Use of lower catalyst loadings resulted in
a pronounced reduction in yield (Table 3, entry 1). Although the
yields for iodophenols (Table 3, entries 2 and 4) are low, it is
encouraging that the reaction works at all given the enhanced
acidity of phenols in water, compared to the situation in a dipolar
aprotic solvent,26 in which we had done all our previous Negishi
cross-coupling reactions with iodophenols.13,27 The ortho-sub-
stituted solid aryl iodides that we employed (2-OH and 2-NH2)
gave only trace amounts of product, probably due to a combina-
tion of slower Negishi cross-coupling and enhanced ease of
protonation of the organozinc reagent.
Table 3. Negishi Cross-Coupling with Solid Aryl Iodides at
65 °C
entry
Ar
ArI mp (°C)
product
yield (%)
1
2
3
4
5
4-ClC6H4
53-54
42-44
33-35
92-94b
50-52
4n
4o
4p
4q
4r
73 (32)a
3-HOC6H4
4-MeC6H4
4-HOC6H4
4-MeOC6H4
28
62
35
51
a Using PdCl2(Amphos)2 (1%). b When this reaction was conducted at
95 °C, only decomposition products were observed.
(3 equiv), aryl iodide (2 equiv), and TMEDA (0.25 equiv), as had
already been established by Lipshutz,10 allowed protected phe-
nylalanine 4a to be obtained in much improved yield (67%, based
on protected iodoalanine 1) (Scheme 2).
Exemplification of the optimized conditions for coupling with
liquid aryl iodides was then undertaken (Scheme 2, Table 1).
Ortho-substituted aryl iodides give poor yields, while other
substrates give moderate yields. This behavior is reminiscent of
the results obtained using our original method for making
phenylalanine derivatives using Pd2dba3/(o-tol)3P in THF as
solvent.25 When the coupling reactions were conducted at 65 °C,
significant improvements in yields were obtained using some
ortho-substituted aryl iodides (Table 1, entries 5 and 6) and also
with several other cases (Table 1, entries 9-11). The conditions
have not been individually optimized for each substrate. In
favorable cases, the palladium loading can be reduced to 1 mol
% without the yield decreasing significantly (Table 1, entry 1).
Two aryl bromides were investigated and gave substantially
lower yields than the corresponding aryl iodides (Table 1, entries
2 and 12).
In all of the examples we have undertaken in aqueous
conditions, the homocoupled product 5 is recovered in variable
yields depending on the aromatic halide used. When protected
iodoalanine 1 was subjected to the cross-coupling conditions, but
in the absence of electrophile, none of the homocoupled product
5 was formed and iodoalanine 1 was recovered. However,
addition of toluene as a cosolvent and warming to 65 °C now
allowed a significant amount of the homocoupled product 5 to be
isolated (Table 4, cf. entries 1 and 2) (Scheme 4). Similar results
could be obtained under nonaqueous conditions using DMF as
Application of the room temperature conditions to 4-chloro-
iodobenzene gave a very disappointing yield of the desired
product 4n (16%) that was significantly lower than expected
based on our previous assessment of the relative reactivity of
iodobenzene and 4-chloroiodobenzene.13 The only significant
difference is the physical state of the electrophile (iodobenzene is
1731
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734

The Journal of Organic Chemistry
ARTICLE
solvent, although warming was now less critical (Table 4, cf.
entries 3 and 4). Interestingly, homocoupling was also observed
in the absence of palladium (Table 4, entry 5) in a reaction that is
the zinc analogue of the Wurtz coupling. In all cases, the mass
balance is protected alanine, arising from protonation of the zinc
reagent 2. Interestingly, treatment of the organozinc reagent 2 in
DMF with iodide 1 in the presence of PdCl2(Amphos)2 gave
none of the expected product 5, from which we can conclude that
a simple sp3-sp3 Negishi cross coupling is not taking place.
Whatever the mechanism, reductive dimerization of iodoalanine
with nano zinc in the presence of TMEDA does provide a simple
method for the formation of the protected bis-amino acid 5.
energies are not generally reported because the existence of many
extremely nonharmonic low-frequency modes for these flexible mole-
cules renders the theoretical thermodynamic data unreliable. The low
energy conformations of the unsolvated alkylzinc iodide are known from
earlier work.1 A series of TMEDA-solvated conformers was generated
from each unsolvated conformer by placing TMEDA in all feasible
positions and orientations around the zinc center. These candidate
conformations were submitted to Gaussian for geometry optimization.
The structures reported in this paper are derived from the resulting low
energy local minima.
Two series of computations were performed. The first set (cf.
Figures 1 and 2) on cationic species in vacuo were corrected for basis
set superposition error (BSSE) using the Boys and Bernardi scheme.15
BSSE corrections did not alter the energy order of the local energy
minima we obtained but did affect the relative energies slightly. The
resulting converged local geometries were used to obtain harmonic
frequencies with BSSE corrections. The overestimation of these fre-
quencies was corrected using the standard scaling approach16,17 with a
scaling factor of 0.98. Spectra were generated with in-house software by
using calculated IR intensities broadened by a Lorentzian of width 15
cm-1. These spectra were compared to the experimental IRMPD
spectra in order to make a structural assignment. The second set of
calculations was carried out on the neutral alkylzinc iodides with
coordinated TMEDA without BSSE corrections. The calculation re-
ported in Figure 5 was carried out in vacuo, while the remaining
calculations (Figures 6-8) use the polarizable continuum model
(PCM)34 to represent the effects of water solvent (ε = 78.3553) using
the integral equation formalism variant (IEFPCM).
’ CONCLUSIONS
In conclusion, we have presented evidence that TMEDA
stabilizes alkylzinc iodides toward protonation in the presence
of water by inducing ionization of the zinc-iodine bond and
have structurally characterized the cation potentially derived
from such ionization in the gas phase. We have also shown that
phenylalanine derivatives can be synthesized using Negishi cross-
coupling in the presence of water, without preformation of the
organozinc reagent. A range of substituents is tolerated by these
conditions, which promise to be useful for the post-translational
modification of peptides in the presence of water.
’ EXPERIMENTAL SECTION
General Cross-Coupling: Method A. Nano zinc dust (190 mg,
3 mmol) was added to a nitrogen-purged round-bottom flask followed
by PdCl2(AmPhos)2 (35 mg, 0.025 mmol). Water (1 mL) was added via
syringe under nitrogen, followed by tetramethylethylenediamine
(23 μL, 0.25 mmol). Aryl iodide (2 mmol) followed by protected iodoala-
nine 1 (329 mg, 1 mmol) were then added with vigorous stirring. The
reaction was allowed to stir at room temperature overnight under
positive pressure of nitrogen. The crude reaction mixture was applied
directly to a silica gel column to afford the purified cross-coupled
product.
Materials. The alkylzinc reagent 2 was prepared as previously
reported1 as a solution in dry dimethylformamide.
Mass Spectrometry. The TMEDA cation 3 is found in the gas
phase after phase transfer with ESI. For the ESI-MS and tandem MS
experiments, aliquots of the alkylzinc iodide solution of 2 were diluted
with dry DMF to sub-millimolar concentrations. For the generation of
TMEDA cation 3, 10 μL of TMEDA was added to 1 mL of the DMF
solution of 2, and this mixture was subjected to ESI after stirring.
Collision-induced dissociation (CID) experiments were performed on a
Finnigan MAT 900 instrument with an EB-QIT configuration
(ThermoFisher, Bremen, Germany) and have been described in detail
elsewhere.1 Exact ion mass measurements were conducted (external
calibration; resolution >20000 fwhm) on a LTQ-Orbitrap instrument
(ThermoFisher) equipped with an ESI ion source. All exact ion masses
were determined with an experimental error e3 ppm.1
Infrared Multiphoton Dissociation Spectroscopy. A 4.7 T
Fourier-transform ion cyclotron resonance (FTICR) mass spectrometer
was used for the IRMPD experiments and has been described in detail
elsewhere.1,28-30
The fragmentation reactions found in IRMPD of the TMEDA cation
3 were analogous to those found upon low energy CID (see Scheme 1).
The IRMPD spectra were recorded by monitoring the most abundant
product ions and the depletion of the respective precursor ion over the
900-1800 cm-1 range. The IRMPD yield was determined from the
General Cross-Coupling: Method B. Nano zinc dust (190 mg,
3 mmol) was added to a nitrogen-purged round-bottom flask followed
by PdCl2(AmPhos)2 (35 mg, 0.025 mmol). Water (1 mL) was added via
syringe under nitrogen, followed by tetramethylethylenediamine
(TMEDA, 23 μL, 0.25 mmol). The aryl iodide (2 mmol) and protected
iodoalanine 1 (329 mg, 1 mmol) were then added with vigorous stirring.
The reaction was heated to 65 °C and stirred for 4 h under positive
pressure of nitrogen. The crude reaction mixture was applied directly to
a silica gel column to afford the purified cross-coupled product.
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-(3-(trifluoro-
methyl)phenyl)propanoate, 4g. Following general cross-cou-
pling, method A using 3-iodobenzotrifluoride (288 μL, 2 mmol) gave,
after purification by silica gel column (5% EtOAc in toluene), 4g (164
mg, 47%) as a red/brown oil, which solidified on standing. Method B
gave 4g (165 mg, 48%): mp 62-64 °C; Rf 0.67 (30% EtOAc in toluene);
IR νmax(film)/cm-1 2978, 1743, 1702, 1500, 1451, 1367, 1326; NMR
δH (400 MHz, CDCl3) 1.43 (9H, s), 3.11 (1H, dd, J = 13.8, 6.1 Hz), 3.24
(1H, dd, J = 13.8, 5.6 Hz), 3.74 (3H, s), 4.63 (1H, dd, J = 13.8, 6.1 Hz),
5.07 (1H, d, J = 7.4), 7.33-7.40 (2H, m), 7.44 (1H, t, J = 7.7 Hz), 7.53
(1H, d, J = 7.6 Hz); δC (101 MHz, CDCl3) 28.2, 38.2, 52.3, 54.3, 80.1,
123.9 (q, J = 3 Hz), 126.2, 128.9, 132.7, 137.2, 154.9, 171.9, two
quaternary carbon signals not observed; [R]22D þ30.8 (c 1.04, CHCl3);
MS m/z (ES) found 348.1433, C16H21NO4F3 requires MHþ 348.1423.
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-(3-chlorophe-
nyl)propanoate, 4h. Following general cross-coupling, method A
using 1-iodo-3-chlorobenzene (247 μL, 2 mmol) gave, after purification
precursor (IP) intensity and the intensity of the product ions (Σ Iproduct ions
)
after laser irradiation at each frequency:
IRMPD yield ¼ ΣIproduct ions=ðIP þ ΣIproduct ions
Þ
ð1Þ
The yield was normalized linearly with laser power to take account of
the change in laser power as a function of photon energy.20
Computational Methods. All electronic structure calculations
were carried out with the Gaussian 09 program package24 using the
B3LYP density functional.31 The Dresden-Stuttgart pseudopo-
tential32,33 was used on Zn and I, and the basis set for all other atoms
was at the 6-311G** level. Only electronic energies are reported. Gibbs
1732
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734

The Journal of Organic Chemistry
ARTICLE
by silica gel column (3% EtOAc in toluene), 4h (139 mg, 44%) as a red/
brown oil. Method B gave 4h (170 mg, 54%): Rf 0.57 (30% EtOAc in
toluene); IR νmax(film)/cm-1 2978, 2927, 1743, 1711, 1502, 1478,
1436, 1366; NMR δH (400 MHz, CDCl3) 1.42 (9H, s), 3.00 (1H, dd, J =
13.9, 6.0 Hz), 3.12 (1H, dd, J = 13.9, 5.6 Hz), 3.73 (3H, s), 4.57 (1H, dd,
J = 13.9, 6.0 Hz), 5.00 (1H, d, J = 7.3 Hz), 6.98-7.03 (1H, m), 7.11 (1H,
s), 7.22 (2H, d, J = 5.0 Hz); NMR δC (101 MHz, CDCl3) 28.3, 38.1,
52.3, 54.3, 80.1, 127.2, 127.5, 129.5, 129.8, 134.3, 138.2, 172.0, one
quaternary carbon not observed; [R]22D 59.4 (c 1.01, CHCl3); MS m/z
(ES) found 314.1171, C15H21NO4Cl requires MHþ 314.1159.
þ48.5 (c 1.03, CHCl3); MS m/z (ES) found 332.1057, C15H20NO4ClF
requires MHþ 332.1065.
’ ASSOCIATED CONTENT
S
Supporting Information. Details of calculated coordi-
b
nates of all reported structures; additional figure S1; ESI-MS
spectrum of the TMEDA cation 3; assignment of peaks to
individual stretching modes in the calculated spectra for cation
3, with axial (Table 5) and equatorial (Table 6) ester groups.
Comparison of NMR chemical shift for the diastereotopic
protons of new substituted phenylalanine derivatives (Table
7), tabulated specific rotations for new phenylalanine derivatives
in CHCl3 (Table 8), experimental for known compounds, and
1H and 13C NMR spectra for compounds 4g-i,k-m and 5. This
information is available free of charge via the Internet at http://
pubs.acs.org.
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-(3,5-difluoro-
phenyl)propanoate, 4i. Following general cross-coupling, method
A using 3,5-difluoroiodobenzene (240 μL, 2 mmol) gave, after purifica-
tion by silica gel column (5% EtOAc in toluene) 4i (129 mg, 41%) as a
red/pink solid. Method B gave 4i (170 mg, 54%): mp 78-80 °C; Rf 0.63
(30% EtOAc in toluene); IR νmax(film)/cm-1 2980, 1743, 1703, 1626,
1596, 1500, 1461, 1438, 1367; NMR δH (400 MHz, CDCl3) 1.41 (9H,
s), 2.99 (1H, dd, J = 13.1, 6.8 Hz), 3.12 (1H, dd, J = 13.8, 5.5 Hz), 3.73
(3H, s), 4.56 (1H, dd, J = 13.4, 6.1 Hz), 5.07 (1H, d, J = 7.4 Hz), 6.60-
6.75 (3H, m); NMR δC (101 MHz, CDCl3) 28.2, 38.1, 52.4, 54.1, 80.2,
102.5 (t, J = 25 Hz), 112.2 (d, J = 13 Hz), 140.0 (t, J = 9 Hz), 155.0, 162.9
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: r.f.w.jackson@sheffield.ac.uk.
(dd, J = 249, 13 Hz), 171.7; [R]22 þ40.4 (c 0.99, CHCl3); MS m/z
D
(ES) found 316.1372, C15H20NO4F2 requires MHþ 316.1360.
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-(4-(trifluoro-
methyl)phenyl)propanoate, 4k. Following general cross cou-
pling method A using 4-iodobenzotrifluoride (294 μL, 2 mmol) gave,
after purification by silica gel column (5% EtOAc in toluene), 4k (146
mg, 42%) as a pink/red solid. Method B gave 4k (147 mg, 42%): mp
78-80 °C; Rf 0.62 (30% EtOAc in toluene); IR νmax(film)/cm-1 2980,
1743, 1703, 1500, 1438, 1367; NMR δH (400 MHz, CDCl3) 1.42 (9H,
s), 3.09 (1H, dd, J = 13.7, 6.4 Hz), 3.22 (1H, dd, J = 13.6, 5.6 Hz), 3.74
(3H, s), 4.64 (1H, dd, J = 13.7, 6.3 Hz), 5.06 (1H, d, J = 7.7 Hz), 7.27
(2H, d, J = 7.9 Hz), 7.56 (2H, d, J = 8.0 Hz); NMR δC (101 MHz,
CDCl3) 28.2, 38.3, 52.4, 54.2, 80.2, 125.4, 129.7, 140.3, 155.0, 171.9, two
quaternary carbon signals not observed; [R]22D þ28.3 (c 1.06, CHCl3);
MS m/z (ES) found 348.1417, C16H21NO4F3 requires MHþ 348.1423.
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-(3,4-difluoro-
phenyl)propanoate, 4l. Following general cross-coupling, method
A using 3,4-difluoroiodobenzene (241 μL, 2 mmol) gave, after purifica-
tion by silica gel column (5% EtOAc in toluene), 4l (161 mg, 51%) as a
red/brown oil, which solidified on standing. Method B gave 4l (166 mg,
53%): mp 49-51 °C; Rf 0.59 (30% EtOAc in toluene); IR νmax(film)/
cm-1 2978, 2926, 1743, 1700, 1610, 1518, 1436, 1366; NMR δH (400
MHz, CDCl3) 1.42 (9H, s), 2.98 (1H, dd, J = 14.1, 6.2 Hz), 3.10 (1H, dd,
J = 14.1, 5.4 Hz), 3.73 (3H, s), 4.55 (1H, dd, J = 13.4, 6.0 Hz), 5.02 (1H,
d, J = 7.3 Hz), 6.80-6.87 (1H, m), 6.90-6.98 (1H, m), 7.07 (1H, m);
NMR δC (101 MHz, CDCl3) 28.3, 37.6, 52.4, 54.3, 80.2, 117.2 (d, J = 17
Hz), 118.2 (d, J = 17 Hz), 125.3 (dd, J = 5, 3 Hz), 133.1, 148.6 (dd, J = 58,
13 Hz), 151.1 (dd, J = 58, 13 Hz), 155.0, 171.9; [R]22D þ59.1 (c 1.02,
CHCl3); MS m/z (ES) found 316.1369, C15H20NO4F2 requires MHþ
316.1360.
’ ACKNOWLEDGMENT
M.S. and F.D. thank Dr. Britta Redlich (FOM Institute) for
assistance and the German Science Foundation (DFG) and the
European Community for funding (FP7/2007-2013; grant no.
226716). We also thank the EPSRC for a DTA studentship (A.J.
R.), Umicore for supplying nano zinc (Nozip), and Professor B.
H. Lipshutz for helpful advice.
’ REFERENCES
(1) Dreiocker, F.; Oomens, J.; Meijer, A. J. H. M.; Pickup, B. T.;
Jackson, R. F. W.; Sch€afer, M. J. Org. Chem. 2010, 75, 1203–1213.
(2) Polfer, N. C.; Oomens, J. Mass Spectrom. Rev. 2009, 28, 468–494.
(3) MacAleese, L.; Maitre, P. Mass Spectrom. Rev. 2007, 26, 583–605.
(4) Fleckenstein, J. E.; Koszinowski, K. Chem.—Eur. J. 2009, 15,
12745–12753.
(5) Koszinowski, K.; B€ohrer, P. Organometallics 2009, 28, 771–779.
(6) Koszinowski, K.; B€ohrer, P. Organometallics 2009, 28, 100–110.
(7) Di Marco, V. B.; Bombi, G. G. Mass Spectrom. Rev. 2006, 25,
347–379.
(8) Caggiano, L.; Jackson, R. F. W.; Meijer, A.; Pickup, B. T.;
Wilkinson, K. A. Chem.—Eur. J. 2008, 14, 8798–8802.
(9) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc.
2009, 131, 15592–15593.
(10) Duplais, C.; Krasovskiy, A.; Wattenberg, A.; Lipshutz, B. H.
Chem. Commun 2010, 46, 562–564.
(11) Lipshutz, B. H.; Abela, A. R.; Boskovic, Z. V.; Nishikata, T.;
Duplais, C.; Krasovskiy, A. Top. Catal. 2010, 53, 985–990.
(12) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 2701–2719.
(13) Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem. 2010, 75,
245–248.
(14) Chalker, J. M.; Wood, C. S. C.; Davis, B. G. J. Am. Chem. Soc.
2009, 131, 16346–16347.
(15) Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553–566.
(16) Irikura, K. K.; Johnson, R. D.; Kacker, R. N. J. Phys. Chem. A
2005, 109, 8430–8437.
(17) Foresman, J. B.; Frisch, A. E. Exploring Chemistry with Electronic
Structure Methods, 2nd ed.; Gaussian, Inc.: Pittsburgh, PA, 1996.
(18) Bythell, B. J.; Dain, R. P.; Curtice, S. S.; Oomens, J.; Steill, J. D.;
Groenewold, G. S.; Paizs, B.; Van, S. M. J. J. Phys. Chem. A 2010, 114,
5076–5082.
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-(3-chloro-4-
fluorophenyl)propanoate, 4m. Following general cross-coupling,
method A using 3 chloro-4-fluoroiodobenzene (255 μL, 2 mmol) gave,
after purification by silica gel column (5% EtOAc in toluene)m 4m (149
mg, 45%) as a red/brown oil, which solidified on standing. Method B
gave 4m (154 mg, 46%): mp 53-55 °C; Rf 0.63 (30% EtOAc in
toluene); IR νmax(film)/cm-1 2979, 1743, 1702, 1500, 1437, 1366;
NMR δH (400 MHz, CDCl3) 1.41 (9H, s), 2.96 (1H, dd, J = 13.9, 6.2
Hz), 3.10 (1H, dd, J = 13.9, 5.5 Hz), 3.72 (3H, s), 4.54 (1H, dd, J = 13.5,
6.1 Hz), 5.04 (1H, d, J = 7.5 Hz), 6.95-7.01 (1H, m), 7.05 (1H, t, J = 8.6
Hz), 7.12-7.20 (1H, m); NMR δC (101 MHz, CDCl3) 28.3, 37.4, 52.4,
54.3, 80.2, 116.6 (d, J = 21 Hz), 120.8 (d, J = 17 Hz), 129.0 (d, J = 7 Hz),
131.4, 133.3 (d, J = 4 Hz), 155.0, 157.3 (d, J = 248 Hz), 171.9; [R]22
D
1733
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734

The Journal of Organic Chemistry
ARTICLE
(19) Lemaire, J.; Boissel, P.; Heninger, M.; Mauclaire, G.; Bellec, G.;
Mestdagh, H.; Simon, A.; Le, C. S.; Ortega, J. M.; Glotin, F.; Maitre, P.
Phys. Rev. Lett. 2002, 89, 273002/1–273002/4.
(20) Drayss, M. K.; Blunk, D.; Oomens, J.; Gao, B.; Wyttenbach, T.;
Bowers, M. T.; Sch€afer, M. J. Phys. Chem. A 2009, 113, 9543–9550.
(21) Asmis, K. R.; Pivonka, N. L.; Santambrogio, G.; Brummer, M.;
Kaposta, C.; Neumark, D. M.; Woste, L. Science 2003, 299, 1375–7.
(22) Oomens, J.; Tielens, A. G. G. M.; Sartakov, B. G.; von, H. G.;
Meijer, G. Astrophys. J. 2003, 591, 968–985.
(23) Polfer, N. C.; Oomens, J.; Moore, D. T.; Von, H. G.; Meijer, G.;
Dunbar, R. C. J. Am. Chem. Soc. 2006, 128, 517–525.
(24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich,
€
S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. Gaussian, Inc.: Wallingford, CT, 2009.
(25) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S.; Elliot, J.;
Mowbray, C. E. J. Org. Chem. 1998, 63, 7875–7884.
(26) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(27) Jackson, R. F. W.; Rilatt, I.; Murray, P. J. Org. Biomol. Chem.
2003, 2, 110–113.
(28) Oepts, D.; Vandermeer, A. F. G.; Vanamersfoort, P. W. Infrared
Phys. Technol. 1995, 36, 297–308.
(29) Polfer, N. C.; Oomens, J. Phys. Chem. Chem. Phys. 2007, 9,
3804–3817.
(30) Valle, J. J.; Eyler, J. R.; Oomens, J.; Moore, D. T.; van der Meer,
A. F. G.; von Helden, G.; Meijer, G.; Hendrickson, C. L.; Marshall, A. G.;
Blakney, G. T. Rev. Sci. Instrum. 2005, 76, 023103.
(31) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(32) Nicklass, A.; Dolg, M.; Stoll, H.; Preuss, H. J. Chem. Phys. 1995,
102, 8942–8952.
(33) Cao, X. Y.; Dolg, M. J. Chem. Phys. 2001, 115, 7348–7355.
(34) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999–3093.
1734
dx.doi.org/10.1021/jo102334c |J. Org. Chem. 2011, 76, 1727–1734