Kinetic studies on the stability and reactivity of β-amino alkylzinc iodides derived from amino acids

Article abstract of DOI:10.1021/jo801754k

(Chemical Equation Presented) β-Amino alkylzinc iodides are intrinsically unstable toward β-elimination and protonation. The aim of this study was to determine the rates of these processes and also to understand how the reactivity of a range of β-amino alkylzinc iodides in Negishi cross-coupling reactions is influenced by the presence of functional groups within the zinc reagent. Decomposition of β-benzamido alkylzinc iodides occurs by protonation, and the first-order rate constant for the self-protonation of the carbon-zinc bond in reagent 4b was determined to be 5.2 × 10^-6 s^-1 (at 291 K). In contrast, the carbamate derivative 2 decomposes by a first-order elimination process. The homologous reagent 3, derived from glutamic acid, decomposes more quickly by β-elimination, with a first-order rate constant of 24 × 10 ^-6 s^-1 (at 291 K). Reagents 23 and 25, in which the Boc group has been replaced with a trifluoroacetyl group, are more stable toward β-elimination than the corresponding reagents 2 and 3, a striking outcome given that the trifluoroacetamido group is a better leaving group. Moreover, this replacement also changes the mechanism of the elimination to a second order process. Pseudo-second-order rate constants for the Negishi cross-coupling of reagents 2, 3, 23, and 25 with iodobenzene have been determined, revealing the higher reactivity of the glutamic acid-derived reagents 3 and 25. The main factor influencing reactivity, therefore, is determined to be the proximity of the ester group, rather than the nature of the nitrogen protecting group. Finally, β-amino alkylzinc iodides 46-48 containing Weinreb amides have been prepared, rate constants for their decomposition through elimination determined, and their synthetic potential for the preparation of β-amino ketones established.

Full text of DOI:10.1021/jo801754k

Kinetic Studies on the Stability and Reactivity of ꢀ-Amino Alkylzinc
Iodides Derived from Amino Acids
Ian Rilatt and Richard F. W. Jackson*
Department of Chemistry, The UniVersity of Sheffield, Dainton Building,
Sheffield S3 7HF, United Kingdom
r.f.w.jackson@shef.ac.uk
ReceiVed August 7, 2008
ꢀ-Amino alkylzinc iodides are intrinsically unstable toward ꢀ-elimination and protonation. The aim of
this study was to determine the rates of these processes and also to understand how the reactivity of a
range of ꢀ-amino alkylzinc iodides in Negishi cross-coupling reactions is influenced by the presence of
functional groups within the zinc reagent. Decomposition of ꢀ-benzamido alkylzinc iodides occurs by
protonation, and the first-order rate constant for the self-protonation of the carbon-zinc bond in reagent
4b was determined to be 5.2 × 10-6 s-1 (at 291 K). In contrast, the carbamate derivative 2 decomposes
by a first-order elimination process. The homologous reagent 3, derived from glutamic acid, decomposes
more quickly by ꢀ-elimination, with a first-order rate constant of 24 × 10-6 s-1 (at 291 K). Reagents 23
and 25, in which the Boc group has been replaced with a trifluoroacetyl group, are more stable toward
ꢀ-elimination than the corresponding reagents 2 and 3, a striking outcome given that the trifluoroacetamido
group is a better leaving group. Moreover, this replacement also changes the mechanism of the elimination
to a second order process. Pseudo-second-order rate constants for the Negishi cross-coupling of reagents
2, 3, 23, and 25 with iodobenzene have been determined, revealing the higher reactivity of the glutamic
acid-derived reagents 3 and 25. The main factor influencing reactivity, therefore, is determined to be the
proximity of the ester group, rather than the nature of the nitrogen protecting group. Finally, ꢀ-amino
alkylzinc iodides 46-48 containing Weinreb amides have been prepared, rate constants for their
decomposition through elimination determined, and their synthetic potential for the preparation of ꢀ-amino
ketones established.
Introduction
γ-amino acids.4 These reagents all give higher yields when
prepared in dipolar aprotic solvents, the most convenient being
DMF. However, each of these ꢀ-amino alkylzinc iodides is
intrinsically unstable toward ꢀ-elimination, forming the corre-
sponding alkene. In addition, such functionalized alkylzinc
iodides can, in principle, decompose either by reaction with
external proton donors or through self-protonation. All these
side-reactions can reduce the yield in desired carbon-carbon
bond-forming reactions. The aim of this study has been to
quantify these effects and also to understand how the reactivity
of a range of ꢀ-amino alkylzinc iodides in Negishi cross-
ꢀ-Amino alkylzinc iodides, derived from enantiomerically
pure amino acids, have proven to be valuable synthetic
intermediates, since they react using Pd or Cu catalysis with a
wide range of electrophiles.1 Reagent 1, derived from serine,2,3
has been widely employed in the synthesis of R-amino acids,
while reagents 2 and 3, derived from aspartic and glutamic acids,
respectively, have been developed for the preparation of ꢀ- and
(1) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 2701–2719.
(2) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. J.
Org. Chem. 1992, 57, 3397–3404.
(3) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S.; Elliot, J.; Mowbray, C. E.
J. Org. Chem. 1998, 63, 7875–7884.
(4) Dexter, C. S.; Jackson, R. F. W.; Elliott, J. J. Org. Chem. 1999, 64, 7579–
7585.
8694 J. Org. Chem. 2008, 73, 8694–8704
10.1021/jo801754k CCC: $40.75 2008 American Chemical Society
Published on Web 10/15/2008

ꢀ-Amino Alkylzinc Iodides DeriVed from Amino Acids
SCHEME 1
prepared from zinc that had been activated with both 1,2-
dibromoethane and chlorotrimethylsilane5 (this value was
calculated using the Arrhenius parameters determined in our
earlier work,5 since we had not made an experimental measure-
ment of the rate constant at 291 K). This result suggests that
the presence of halide ions can adversely influence the stability
of ꢀ-amino alkylzinc iodides toward elimination. This finding
is consistent with the improved results obtained for copper-
promoted reactions of ꢀ-amino alkylzinc iodides when using
catalytic amounts of CuBr ·DMS,8 rather than stoichiometric
amounts of CuCN ·2LiCl.9
FIGURE 1. Kinetic analysis of the decomposition of organozinc
reagent 2 in DMF-d7 according to a first-order fit.
coupling reactions is influenced by the presence of functional
groups within the zinc reagent. We have previously established
that reagent 1 is the most stable of the three reagents3 and have
therefore concentrated on the behavior of reagents 2 and 3.
Hammett Study of Benzamide Decomposition. In previous
work,5 the activation parameters for the first-order elimination
of alkylzinc reagent 2 were determined in both THF and DMF.
The negative entropy of activation was interpreted as indicating
that a syn-elimination pathway is followed, in which coordina-
tion of the carbamate carbonyl group to zinc is required (eq 1).
This coordination would be expected to have two consequences,
namely increased electron density at zinc (thereby weakening
the carbon-zinc bond) and enhancement of the leaving group
ability of the carbamate, through Lewis acid activation.
Results and Discussion
We have previously studied the decomposition of the less
stable reagent 2 using 1H NMR spectroscopy, establishing that
the main decomposition pathway is a unimolecular elimination
reaction in both DMF-d7 and THF-d8. In our original kinetic
work,5 ꢀ-amino alkylzinc iodides were prepared from the
corresponding alkyl iodides using zinc activated by prior
treatment with 1,2-dibromoethane and chlorotrimethylsilane.6
Recent preparative work has established that, at least in DMF,
the use of 1,2-dibromoethane is unnecessary, and consequently,
for all of the reactions reported in this paper, activation of zinc
was carried out using chlorotrimethylsilane alone. This proce-
dure, adapted from Hiemstra’s protocol,7 involves removal of
the DMF (containing residual chlorotrimethylsilane and ZnCl2)
followed by drying of the activated zinc under vacuum and has
the advantage that cheap undeuterated DMF can be used for
the activation process. In order to establish the influence of this
change in activation protocol on the elimination rate, the
alkylzinc iodide 2 was prepared, and its elimination (at 291 K)
In order to probe further the mechanism of the elimination
reaction, we undertook a study of the decomposition of a range
of ꢀ-amino alkylzinc iodides 4a-e, in which the amino group
was protected as a para-substituted benzamide, since the results
should be amenable to Hammett analysis. The alkyl iodides
5a-e, precursors of the alkylzinc iodides 4a-e, were prepared
from the iodide 6 by Boc-deprotection and acylation. The overall
yields for this process were poor due to rapid cyclization of the
product iodides leading to the corresponding oxazolines 7a-e
(Scheme 1), but pure samples of all the iodides could be
obtained. As expected, the more electron-rich substrates cyclized
very readily, and in the case of the 4-methoxy derivative 5e,
cyclization was so rapid that a 1H NMR spectrum (in DMF-d7)
obtained within 1 min of sample preparation showed ap-
proximately 50% of the oxazoline 7e.
1
was followed by H NMR by measuring the integral of the
methylene protons adjacent to zinc, relative to an internal
standard (mesitylene). A small inflection was observed at the
beginning of the first order plot (Figure 1), which was attributed
to competing initial protonation of the alkylzinc iodide 2, due
to extraneous proton sources introduced during the transfer of
the sample into the NMR tube. The first-order rate constant for
the elimination reaction was determined to be 8.9 × 10-6 s-1
,
following linear least-squares regression analysis. This contrasts
with a value of 12.0 × 10-6 s-1 (at 291 K) for the same reagent
(5) Dexter, C. S.; Hunter, C.; Jackson, R. F. W.; Elliott, J. J. Org. Chem.
2000, 65, 7417–7421.
(6) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988,
(8) Hunter, C.; Jackson, R. F. W.; Rami, H. K. J. Chem. Soc., Perkin Trans.
1 2001, 1349–1352.
(9) Dunn, M. J.; Jackson, R. F. W.; Pietruszka, J.; Turner, D. J. Org. Chem.
1995, 60, 2210–2215.
53, 2390–2392.
(7) Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J.; Hiemstra, H. Synlett 1998,
1126–1128.
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Rilatt and Jackson
TABLE 1. Preparation of Benzamides 5
benzamide
X
overall yield, %
5a
5b
5c
5d
5e
CN
Br
H
CH3
CH3O
23
25
26
19
18
Notwithstanding this instability, each of the iodides 5a-e
was efficiently converted into the corresponding zinc reagent
4a-e, whose decomposition was then followed using 1H NMR
spectroscopy (eq 2). Rather surprisingly, no evidence for
elimination was apparent in any example, but instead a simple
protonation reaction occurred to give the products 8a-e. In
particular, the progress of protonation of the alkylzinc iodide
4b (X ) Br) was monitored up to 90% conversion (over 4 days)
to allow differentiation between first- and second-order pro-
cesses. Analysis of the data using linear least-squares regression
analysis (Figure 2) clearly established that the protonation was
first order, with a rate constant of 5.2 × 10-6 s-1. (We are not
aware of a previous determination of a rate constant for the
protonation of a carbon-zinc bond.) The most credible inter-
pretation of the small initial inflection in the plot is that this
arises due to proton sources introduced during the transfer of
the sample into the NMR tube. The decomposition of three other
examples (4a, 4c, and 4e) to give the corresponding protonated
products (8a, 8c, and 8e) was followed to around 35%
conversion which, although insufficient to allow unambiguous
determination of the reaction order, was enough to determine
apparent first order rate constants, by analogy with reagent 4b.
In each case, the first-order rate constant was found to be very
similar to that determined for 4b and therefore essentially
independent of the substituent X.
FIGURE 3. Appearance of CH2ZnI in the 1H NMR spectra of reagents
4a-e in DMF-d7.
FIGURE 4. Plot of ∆δ for the CH2ZnI group in reagents 4a-e against
the Hammett parameter σx.
occurs by self-protonation. A possible mechanism involves
tautomerisation of the amide in zinc reagent 4 into the enol
form, so that intramolecular protonation of the carbon-zinc
bond can occur (eq 3).
While this data is consistent with protonation by an external
proton source present in substantial excess, this is unlikely given
that the reactions were conducted in a sealed NMR tube. It
therefore appears that the subsequent decomposition process
Although the benzamide study had not provided any insight
into the elimination reaction of ꢀ-amino alkylzinc iodides, it
had allowed the determination of the kinetics of a potentially
competing protonation reaction. In addition, an interesting
pattern was observed in the 1H NMR spectra for the methylene
group adjacent to zinc [CH2ZnI] throughout the series of
reagents 4a-e, connecting the Hammett parameter of the aryl
substituent, σx, to the difference in chemical shift of the two
protons (Figure 3). A plot of ∆δ (the difference in chemical
shift between the signals for the two diastereoisotopic signals)
against σx showed a significant correlation (Figure 4).
While the magnitude of the difference in chemical shift values
(∆δ) for diastereotopic protons is affected by numerous factors,
including molecular conformation, temperature, and solvent, it
is not generally possible to relate quantitatively the degree of
nonequivalence to molecular structure.10 However, in this case,
it appears that the nature of the benzamide para substituent does
influence the observed NMR spectra in a predictable way. The
fact that ∆δ is largest for the p-methoxy derivative is entirely
FIGURE 2. First-order plot for the (self-)protonation of reagent 4b in
DMF-d7.
(10) Jennings, W. B. Chem. ReV. 1974, 75, 307–322.
8696 J. Org. Chem. Vol. 73, No. 22, 2008

ꢀ-Amino Alkylzinc Iodides DeriVed from Amino Acids
FIGURE 6. Kinetic analysis of the decomposition of organozinc
reagent 3 in DMF-d7 according to a second order fit.
FIGURE 5. Kinetic analysis of the decomposition of organozinc
reagent 3 in DMF-d7 according to a first order fit.
adjacent to zinc. This problem was overcome by the use of
Specfit, a program developed for data collection and analysis
in stopped-flow experiments using UV spectroscopy. By adapt-
ing the use of the program, it was possible to capture the values
for the NMR integrals for the species present at each time point
in the kinetic experiment. The initial concentration of each
component was calculated from the ratio of the integrals and
the initial concentration of the alkyl iodide. The change in
concentration of each species over time was then measured
(Figure 7), and the rate constant for each process, as well as
the deviation from a calculated fit, was determined. The integrals
were normalized to represent the same number of protons and
the initial concentration of exogenous protons in the reaction
medium was calculated from the integral of the protonated
product at the end of the experiment.
Initially, a poor fit was observed between the experimental
and calculated data using Specfit when the concentrations of
zinc reagent, alkene byproduct, and protonated material were
each taken into account. This primary analysis indicated a
deficiency in the measured amounts of reagent 3 and the
elimination product 9 toward the end of the experiment,
compared to the calculated values (see the Supporting Informa-
tion). This was attributed to the appreciable volatility of the
elimination product, methyl 3-pentenoate 9 (bp 55-56 °C)
which might be expected to diffuse into the headspace of the
NMR tube where it would remain undetected. However, the
ester 9 was detected by mass spectroscopy, and its odor was
very evident in the NMR tube after completion of the experi-
ment. An analysis of the kinetic data taking this into consid-
eration, using only the concentration of zinc reagent 3 and
protonation product 10, resulted in theoretical and experimental
data in very good agreement (Figure 8).
consistent with the expected enhancement of coordination of
the amidic carbonyl group to zinc, suggesting that this interaction
is the principal determinant responsible for the observed pattern.
The fact that none of the zinc reagents 4a-e showed evidence
of decomposition via elimination demonstrates the substantial
impact on stability of replacing the carbamate group in reagent
2 with a benzamide and suggested that rather subtle changes in
the nitrogen protecting group might exert a profound influence
on the behavior of ꢀ-amino alkylzinc iodides. Indeed, Knochel
has previously reported that higher yields of coupling product
are obtained using a simple ꢀ-benzamido alkylzinc iodide
compared with those obtained from the corresponding aceta-
mido-derivative.11
Study of the Decomposition of Organozinc Reagent 3.
Attention now turned to the glutamic acid-derived alkylzinc
iodide 3, which was prepared in DMF-d7, and its decomposition
1
followed by H NMR spectroscopy, as described above. The
alkylzinc iodide 3 was found to decompose by 95% over the
course of 24 h, substantially faster than reagent 2, and it was
therefore straightforward to compare a first- and second-order
fitting in a rigorous manner. The first-order plot (Figure 5) shows
that the decomposition was principally a first-order elimination
reaction, leading to methyl 4-pentenoate 9, although there was
evidence for small amounts of the protonation product 10 (eq
4). The overall first-order decomposition rate constant, k, was
determined by linear least-squares regression analysis to be 29
× 10-6 s-1, substantially larger than the corresponding rate
constant for the decomposition of reagent 2. The second-order
plot (Figure 6) clearly demonstrates the need to monitor the
decomposition for more than one-half-life: approximately 50%
of the zinc reagent had decomposed after 8 h, and both analyses
produce a credible straight line plot over this time.
Analysis of the data for decomposition of 3 using Specfit
showed that the rate constant for the elimination process was
24 × 10-6 s-1. Given the overall first-order decomposition rate
constant, k, of 29 × 10-6 s-1, an upper limit of 5 × 10-6 s-1
can be defined for the rate constant for the corresponding
protonation reaction to give 10, very similar to that determined
for protonation of the 4-bromobenzamide derivative 4b (5.2 ×
10-6 s-1). Reanalysis of the data for the decomposition of
reagent 2 using Specfit gave a first-order rate constant for the
elimination of 9 × 10-6 s-1 (cf. 8.9 × 10-6 s-1, the overall
decomposition rate constant previously determined), showing
that protonation of reagent 2 is not significant.
One limitation of this method of analysis is that the resulting
decomposition rate also contains a component for the competing
protonation of the zinc reagent and any other processes that
result in a change in chemical shift of the methylene protons
(11) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger, S.;
Knochel, P. Tetrahedron 1994, 50, 2415–2432.
J. Org. Chem. Vol. 73, No. 22, 2008 8697

Rilatt and Jackson
FIGURE 7. Kinetic analysis of the decomposition of organozinc reagent 3 in DMF-d7 using Specfit.
SCHEME 2. Synthesis of Iodides 21 and 22
FIGURE 8. Plot of measured vs calculated values for the RCH2ZnI
integral, using the concentrations of zinc reagent 3 and protonated
product 10.
Alikelyexplanationforthelowerstabilityofglutamate-derived
reagent 3 is reduced coordination by the ester carbonyl group
to zinc in this compound, which results in the formation of a
7-membered ring 11, compared to the lower homologue 2
derived from aspartic acid which would exist as a 6-membered
ring 12. Evidence for ester co-ordination has been provided
through 13C NMR studies4 and is expected to compete with
coordination by the Boc group to zinc, thereby reducing the
rate of elimination to a greater extent in the case of reagent 2.
logues of the zinc reagents 2 and 3, incorporating different
N-protecting groups, was carried out according to the protocols
already described. A preliminary account of a part of this work
has appeared.12
A good candidate for the replacement of the tert-butoxycar-
bonyl group in compounds 2 and 3 was the trifluoroacetyl (TFA)
group. As well as reducing, very substantially, the Lewis basicity
of the carbonyl group, the amide proton should be much more
acidic than that of a simple carbamate and offer an interesting
test of the tolerance of organozinc iodides toward acidic protons.
Accordingly, aspartic acid methyl ester hydrochloride 13, and
glutamic acid methyl ester 14 were each converted into the
corresponding N-TFA derivatives, 15 and 16, and the free
carboxyl group was then reduced, via the N-hydroxysuccinimide
esters, 17 and 18, to give the corresponding alcohols 19 and
20. Treatment of the alcohols 19 and 20 under standard
iodinating conditions gave the precursor alkyl iodides 21 and
22 (Scheme 2).
Stabilizing ꢀ-Amino Alkylzinc Iodides. Having established
reliable methods for studying the decomposition of ꢀ-amino
alkylzinc iodides, attention turned to evolving one or more
strategies to inhibit these competing pathways so as to increase
the yields of desired products in synthetic transformations. Our
working hypothesis suggested that replacement of the carbamate
group with one containing a less Lewis basic carbonyl group
would result in reduced co-ordination and thereby depress the
rate of elimination to provide more stable ꢀ-amino alkylzinc
reagents. A comparative study of the decomposition of ana-
Reaction of the iodide 21 with activated zinc in DMF-d7 gave
the corresponding organozinc reagent 23. Interestingly, the
(12) Jackson, R. F. W.; Rilatt, I.; Murray, P. J. Chem. Commun. 2003, 1242–
1243.
8698 J. Org. Chem. Vol. 73, No. 22, 2008

ꢀ-Amino Alkylzinc Iodides DeriVed from Amino Acids
possible explanation for the observed behavior is that, rather
than the alkylzinc halide 23, it is instead the corresponding
dialkylzinc species 24, (formed through fast Schlenk pre-
equilibrium), which undergoes the elimination reaction (eq 5).
Although the NMR spectra are consistent with the major solution
species being the alkylzinc iodide, the equilibrium concentration
of the dialkylzinc species 24 is related to the square of the
concentration of the alkylzinc iodide 23, explaining the observed
second-order dependence. The observed change in mechanism
probably arises from the reduced ability of the carbonyl oxygen
of the trifluoroacetamide group to coordinate to zinc (cf. the
NMR evidence in Figure 9) and therefore to promote the syn-
elimination believed to occur in the case of the corresponding
Boc derivative 2. The alternative elimination pathway for a
ꢀ-amino alkylzinc iodide, namely anti-elimination, is less likely
to occur due to the electron-withdrawing character of the iodide
ligand (which in turn reduces the electron density at the carbon
atom bound to zinc). However, the dialkylzinc species 24,
lacking the influence of the iodide ligand, is better able to
undergo anti-elimination. Whatever the reason, the second-order
nature of the elimination process for 23 means that higher
reagent concentrations lead to faster decomposition. This stands
in marked contrast to the analogous Boc derivative 2, where
high concentrations are optimal to promote the bimolecular
processes involved in bond-forming reactions.
FIGURE 9. 1H NMR signals for indicated protons of 2 and 23 in DMF-
d7. Reproduced with permission from The Royal Society of Chemis-
try.12
FIGURE 10. Plot of apparent first-order rate constants for the
decomposition of reagent 23 against initial concentration, confirming
that the decomposition is second order.
The rate of decomposition of the glutamic acid-derived
alkylzinc reagent 25 was then investigated, and as expected,
this compound decomposed to give methyl 4-pentenoate 9, albeit
rather slowly. The extent of decomposition of 25 was, therefore,
insufficient to assign an order to the elimination reaction
rigorously, but it is reasonable to assume, by analogy with the
elimination of reagent 23, that a second-order reaction takes
place. The (assumed) second-order rate constant (determined
using Specfit) for the elimination of the glutamic acid-derived
alkylzinc reagent 25 was 3.3 ( 0.5 × 10-6 M-1 s-1, very similar
to that observed for the lower homologue 23. Replacement of
the Boc group in compound 3 by the TFA group had resulted
therefore, as predicted, in a reagent, 25, which was substantially
more stable toward elimination.
appearance of the signal (a simple doublet) for the two protons
adjacent to zinc in the H NMR spectrum of reagent 23 was
1
radically different from that observed in reagent 2 (Figure 9).
More pertinently, the trifluoroacetamide 23 proved to be more
stable toward ꢀ-elimination than the original reagent 2 (by a
1
factor of more than 3-fold), as assessed by H NMR spectros-
copy. However, as a result of this enhanced stability, it became
more challenging to monitor the decomposition over 2 half-
lives due to the amount of instrument time required (zinc reagent
23 decayed by just 50% over 60 h). In our original interpretation
of the data,12 the elimination reaction was assumed to be a first-
order process, by analogy with the corresponding Boc derivative.
However, when the decomposition of reagent 23 was followed
at a range of initial concentrations, the apparent first-order rate
constants varied. A plot of these rate constants against concen-
tration (Figure 10) gave a straight line, passing through the
origin. Linear least-squares regression analysis indicated a
second-order rate constant for the decomposition of reagent 23
of 3.8 ( 0.5 × 10-6 M-1 s-1. Analysis of the data at each of
these concentrations using Specfit indicated a second-order rate
constant of 2.8 ( 0.2 × 10-6 M-1 s-1 for the elimination
process, entirely consistent with the slightly larger overall
decomposition rate constant.
Comparison of the 13C NMR spectra of the N-TFA-protected
zinc reagents with their N-Boc counterparts revealed that the
carbonyl oxygen-zinc interaction had been suppressed (Table
2). Interestingly, no significant differences in ester coordination,
as revealed by the measurement of the ∆δ values for the ester
and amide/carbamate carbonyl groups, were observed for each
pair of zinc reagents.
Reactivity of Organozinc Reagents in Negishi Cross-
Coupling. Having established the influence of the nitrogen
protecting group on stability, the next goal was to understand
The observation that introducing the TFA protecting group
had not only reduced the rate of the elimination reaction but
had also altered the mechanism of the process provided clear
evidence of the pivotal role of the nitrogen protecting group in
determining the properties of ꢀ-amino alkylzinc iodides. A
J. Org. Chem. Vol. 73, No. 22, 2008 8699

Rilatt and Jackson
TABLE 2. Changes in 13C NMR Chemical Shift of Carbonyl
Groups upon Zinc Insertion in DMF-d7 for Zinc Reagents 2, 23, 3,
and 25
∆δ CdO (δ(R-ZnI) - δ(R-I)
)
2
23
3
25
N-protecting group
ester
-0.5
+0.9
-1.9
+1.0
-0.7
+0.1
-1.8
+0.5
how this change affected the reactivity of ꢀ-amino alkylzinc
iodides in Negishi cross-coupling reactions. It has been estab-
lished that the rate-limiting step in the Negishi reaction is the
transmetalation step, in which the organic group is transferred
from zinc to palladium.13 While the second-order rate constant
for the stoichiometric reaction between (Ph3P)2Pd(I)Ph and (E)-
1-octenylzinc chloride to give (E)-1-octenylbenzene has been
determined (2.9 M-1 min-1 ) 4.83 10-2 M-1 s-1),13 there is
rather little experimental rate data for Negishi cross-coupling
reactions conducted under catalytic conditions.14 We were
pleased to discover that NMR spectroscopy, in combination with
data analysis using Specfit, allowed the measurement of pseudo-
second-order constants, k, for the cross-coupling reaction of the
four reagents 2, 3, 23, and 25 with iodobenzene, catalyzed by
Pd2(dba)3 and P(o-tol)3 (eq 6), according to the rate law in eq
7, at particular concentrations of palladium and phosphine
ligand.
FIGURE 11. Plot of measured versus calculated values for the product
integral of the reaction of reagent 23 with PhI.
TABLE 3. Comparison of Elimination Rate Constants, Reaction
Rate Constants, and Isolated Yield from Negishi Cross-Coupling
with Iodobenzene
elimination
rate constant
reaction
isolated
yieldb
(%)
organozinc N-protecting (×10-6 s-1 or
rate constanta
(×10-4 M-1 s-1
reagent
group
×10-6 M-1 s-1
)
)
2
Boc
TFA
Boc
TFA
9.0
2.8
24.0
3.3
0.6
0.6
4.3
7.5
51
55
59
79
23
3
25
a Pseudo-second-order rate constant determined at 291 K using 0.42
mol % Pd2(dba)3 and 1.67 mol % P(o-tol)3 as catalyst. b All yields are
based on starting alkyl iodide.
(in an NMR tube), and represent a lower limit to the efficiency
of the process (vide infra). Also included for reference are the
rate constants determined for the elimination reactions. It is
noteworthy that the rate constants for the catalytic cross-coupling
of zinc reagents 2, 3, 23, and 25 with iodobenzene are similar
in magnitude to the rate constant for the stoichiometric reaction
between (Ph3P)2Pd(I)Ph and (E)-1-octenylzinc chloride (vide
supra), when the amount of palladium catalyst (0.84 mol %) is
taken into account (4.83 10-2 M-1 s-1 × 8.4 10-3 ) 4.1 10-4
M-1 s-1). This provides circumstantial evidence that, at least
for the catalytic cross-coupling reactions included in the present
study, it is the transmetalation step that is rate-limiting, and the
main factor determining the efficiency of the cross-coupling
procedure, rather than the stability of the reagent. Nonetheless,
it is interesting that the lower stability, but higher reactivity, of
reagent 3 results in a similar isolated yield to that obtained with
reagent 23. It appears that the rate of the cross-coupling reaction
is primarily dependent upon the proximity of the ester group,
rather than the nature of nitrogen protecting group, since both
glutamic acid derived reagents 3 and 25 are substantially more
reactive than the aspartic acid derivatives 2 and 23.
Preparative Negishi Cross-Coupling Reactions. When
preparative Negishi cross-coupling reactions of reagent 23 were
carried out with aryl iodides, the isolated yields of the products
26 were consistent, and also broadly similar to those previously
obtained with reagent 2 (Scheme 3, Table 4). In the case of
4-iodonitrobenzene, no product was obtained under standard
conditions, probably due to competing reduction of the nitro
group with metallic zinc. To avoid this, the solution of the
reagent 23 was transferred via syringe to a separate flask, leaving
behind excess zinc, and reacted with the electrophile under
standard conditions to furnish the product in 65% yield. This
leads to the conclusion that, while reagent 23 is more stable
toward ꢀ-elimination than reagent 2, its overall efficiency in
rate ) k[RZnI][PhI]
(7)
In contrast to the kinetic analysis of the elimination reaction,
a significant technical challenge was the short time frame within
which the Negishi reactions of some of the reagents went to
completion. When typical catalyst loadings were used [2.5 mol
% of Pd2(dba)3 and 10 mol % of P(o-tol)3], the cross-coupling
reactions were essentially complete by the time the first NMR
spectrum was recorded. This obstacle was straightforwardly
overcome by reducing the catalyst loading15 by a factor of 6
[to 0.42 mol % of Pd2(dba)3 and 1.67 mol % of P(o-tol)3].
Using Specfit, we observed a good correlation between
the experimental and theoretical values of the integrals
of the diagnostic signals in the 1H NMR spectra (specifically
the benzylic protons in the product), although a slight increase
in reaction rate toward the end of the experiment was
observed (Figure 11). The deviation in reaction rate over the
course of the reaction may be due to a number of factors,
including the change in concentration of ZnI2 affecting the
Schlenk equilibrium16 and catalyst/ligand equilibria or matrix
effects, in turn due to the relatively high concentrations at
which the reactions were conducted.
Pseudo-second-order rate constants for the Negishi cross
coupling of reagents 2, 3, 23, and 25 with iodobenzene,
according to eq 7, are given in Table 3, together with yields of
isolated products from the NMR experiment. These yields are
obtained from reactions conducted under suboptimal conditions
(13) Negishi, E.; Takahashi, T.; Baba, S.; Vanhorn, D. E.; Okukado, N. J. Am.
Chem. Soc. 1987, 109, 2393–2401.
(14) Casares, J. A.; Espinet, P.; Fuentes, B.; Salas, G. J. Am. Chem. Soc.
2007, 129, 3508–3509.
(15) Huang, Z.; Qian, M.; Babinski, D. J.; Negishi, E.-i. Organometallics
2005, 24, 475–478.
(16) Denmark, S. E.; O’Connor, S. P. J. Org. Chem. 1997, 62, 3390–3401.
8700 J. Org. Chem. Vol. 73, No. 22, 2008

ꢀ-Amino Alkylzinc Iodides DeriVed from Amino Acids
SCHEME 3. Preparation of ꢀ-Amino Acids 26 by Negishi
Cross-Coupling
SCHEME 5. Preparation of γ-Amino Acids 28 by Negishi
Cross-Coupling
TABLE 4. Negishi Cross-Coupling of Reagent 23 with Aryl
Iodides
TABLE 5. Negishi Cross-Coupling of Reagent 25 with Aryl
Iodides
yielda (%)
aryl iodide
product
Ar
yield,a
%
aryl iodide
product
Ar
4-MeC6H4I
4-MeOC6H4I
4-O2NC6H4I
PhI
4-NCC6H4I
1-NaphthylI
4-BrC6H4I
4-FC6H4I
26a
26b
26c
26d
26e
26f
4-Me-C6H4
4-MeOC6H4
4-O2NC6H4
Ph
4-NCC6H4
1-naphthyl
4-BrC6H4
4-FC6H4
64 (73)b
69 (68)b
65 (89)b
72 (73)b
77 (-)
4-MeC6H4I
4-MeOC6H4I
PhI
2-H2NC6H4I
2-FC6H4I
28a
28b
28c
28d
28e
4-MeC6H4
4-MeOC6H4
Ph
2-H2NC6H4
2-FC6H4
79 (68)b
79 (68)b
88 (68)b
62 (56)b
51 (34)b
70 (61)b
53 (58)b
74 (65)b
a All yields are based on the starting alkyl iodide 22. b Yields in
parentheses obtained using reagent 3 and reported previously.4
26g
26h
a All yields are based on the starting alkyl iodide 21. b Yields in
parentheses of the corresponding Boc-derivative obtained using reagent
2 and reported previously.4
SCHEME 6. Preparation of N-Boc-Protected Weinreb
Amide 33
SCHEME 4
cross-coupling reactions, the key parameter, is similar. Nonethe-
less, reagent 23 does allow access to ꢀ3-amino acids 26
containing a base-labile nitrogen protecting group, and so may
offer practical advantages of orthogonality in synthetic applica-
tions.
In order to demonstrate that the no racemisation had occurred
during the Negishi reaction, the naphthyl derivative 26f was
converted into the previously reported N-Boc derivative 27 (93%
overall)4 by treatment with NaOMe in MeOH, followed by
isolation of the hydrochloride salt, and standard Boc protection
(Scheme 4). Measurement of the optical rotation and comparison
with the literature value4 revealed that no detectable racemiza-
tion had occurred.
As established in the present study, replacement of the Boc-
group in reagent 3 with a trifluoroacetyl group in reagent 25
results in an intermediate that is not only more stable with
respect to elimination but also slightly more reactive in the
Negishi cross-coupling. This combination ensured that excellent
yields of γ-amino acids 28 were obtained in preparative cross-
coupling of reagent 25 with a range of aryl iodides (Table 5,
Scheme 5). The increase in yield when using reagent 25
compared to 3 for the coupling with 2-fluoroiodobenzene, a
normally inefficient substrate in such processes, is significant.
Of the ꢀ-amino alkylzinc iodides prepared to date, reagent 25
is likely to display the least significant intramolecular coordina-
tion of zinc by the carbonyl group of either the ester (formation
of a 7-membered ring, cf. 11) or the trifluoroacetamide, thereby
diminishing the two factors which suppress the reactivity of
the reagent.
exerted by the carboxylic acid function. The initial hypothesis
was that replacement of the ester with an alternative functional
group able to coordinate zinc more strongly might provide
reagents stabilized toward elimination, especially in cases where
carbamate coordination had been implicated in this decomposi-
tion pathway. In the case of the trifluoroacetyl reagents, the
outcome was less obviously predictable, since elimination did
not appear to proceed by coordination of the nitrogen protecting
group to zinc. The group selected to replace the ester was the
Weinreb amide,17 given its well-established pedigree as a metal
coordinating group,18,19 as well as its value for further synthetic
manipulation.
Synthesis of the required N-Boc-protected Weinreb amide
33 started from commercially available N-Boc aspartic acid
R-benzyl ester 29 (Scheme 6). Weinreb amide 30 was formed
in quantitative yield by reaction with N,O-dimethylhydroxy-
lamine hydrochloride, according to the literature procedure.20
The benzyl ester was cleaved by hydrogenation and the resulting
acid 31 was reduced to alcohol 32 via sodium borohydride
reduction of a mixed anhydride and converted into the iodide
33 under standard conditions.
Influence of the Carboxylic Acid on the Stability and
Reactivity of ꢀ-Amino Alkylzinc Iodides. Having established
the substantial influence that the nitrogen-protecting group can
have on the behavior of ꢀ-amino alkylzinc iodides derived from
aspartic and glutamic acid, attention was focused on the effect
(17) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(18) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15–40.
(19) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342,
340–347.
(20) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J. J. Chem.
Soc., Perkin Trans. 1 1999, 855–866.
J. Org. Chem. Vol. 73, No. 22, 2008 8701

Rilatt and Jackson
SCHEME 7
SCHEME 9
TABLE 6. Changes in 13C-NMR Chemical Shift of Carbonyl
Groups upon Zinc Reagent Formation in DMF-d7 for Weinreb
amides
SCHEME 8. Preparation of Iodides 44 and 45
∆δ CdO (δ(R-ZnI) - δ(R-I)
)
46
47
48
N-protecting group
Weinreb amide
-0.3
+2.9
-1.8
+2.5
-1.9
+0.7
derivatives 46 and 47 but not for the glutamic acid homologue
48 (Table 6). In this system, it is hard to exclude the possibility
that such a shift may also be due to a hydrogen-bonding
interaction between the Weinreb amide and the NH residue.
The shifts in the Boc4 and TFA (this work) carbonyl carbon
signals upon zinc insertion were typical of those already
observed.
Contrary to our expectations, all three zinc reagents 46, 47,
and 48 proved to decompose more quickly than the correspond-
ing methyl ester analogues, and it was therefore possible in each
case to follow the elimination reaction to 90% completion,
allowing a definitive assessment of the order of the elimination
reaction. The Boc Weinreb amide derivative 46 decomposed
by a first-order process as expected, albeit with a rate constant
of 62.5 × 10-6 s-1, some 7 times larger than the elimination
rate constant for the corresponding methyl ester 2. However, it
was surprising that both trifluoroacetyl derivatives 47 and 48
also decomposed via first order processes, with rate constants
of 8.1 × 10-6 s-1 and 10.4 × 10-6 s-1, respectively.
Direct comparison of the first-order rate constants for
decomposition of reagents 46 and 47 shows unambiguously that
the trifluoroacetamido reagent 47 is substantially more stable
than the Boc-derivative 46. This result, for two reagents that
are directly comparable, demonstrates clearly that the key
parameter in promoting elimination of ꢀ-amino alkylzinc
iodides, by a first-order process, is the Lewis basicity of the
nitrogen protecting group and not its intrinsic leaving group
ability.
There are two possible rationalizations for the decrease in
stability of the zinc reagents containing a Weinreb amide. In
principle, the elimination can occur from either of two confor-
mations. In pathway A, a hydrogen bond between the acidic
trifluoroacetamide proton and the Weinreb amide (observed in
a related system22) organizes the system in a conformation
disposed toward syn-elimination, despite the poor Lewis basicity
of the trifluoroacetyl group. In pathway B, the strongly
coordinating Weinreb amide might increase the electron density
on zinc sufficiently to allow a normal anti-elimination to take
place (Scheme 10). Although the 13C NMR evidence suggests
that the trifluoroacetyl group does not coordinate to zinc, the
reactive conformation may, of course, not be the major solution
structure, so it is not possible to exclude pathway A on this
basis alone.
The synthesis of the N-TFA-protected, aspartic acid-derived
Weinreb amide used a similar protocol, starting from the Boc-
protected Weinreb amide 30. The analogous glutamic acid
derived Weinreb amide derivative 35 was synthesized from
commercially available protected glutamic acid 34 (Scheme 7)
using the same procedure employed for the preparation of 30.
Benzyl esters 30 and 35 were converted into the TFA
derivatives 36 and 37, respectively, which were then transformed
into the carboxylic acids 38 and 39 in quantitative yield by
hydrogenation (Scheme 8). Although problems were encoun-
tered upon attempted reduction of the carboxylic acids 38 and
39 using the mixed anhydride protocol used previously, reduc-
tion via the N-hydroxy succinimide esters was achieved.
However, in the case of the aspartic acid derivative, reduction
to the alcohol 42 proceeded in low yield (25%) due to loss of
the trifluoroacetyl group under the reaction conditions. Although
such deprotections are known, more forcing conditions (reflux)
are normally required.21 Reduction of the glutamic acid homo-
logue proceeded more efficiently to give alcohol 43 in an
unoptimised yield of 52% over two steps. Iodination of alcohols
42 and 43 proceeded smoothly to give the desired iodides 44
and 45.
The alcohol 42 was subsequently synthesized more efficiently
via a protecting group transformation of the Boc-protected ꢀ
amino alcohol 32, involving deprotection/reprotection in excess
of trifluoroacetic anhydride (Scheme 9).
The precursor iodides 33, 44, and 45, were transformed into
the zinc reagents 46-48 and a comparison made of their 13C
NMR spectra. Evidence for a significant interaction between
the Weinreb amide and zinc was provided by a shift in the 13
C
signal due to the amide carbonyl group for both aspartic acid
(22) Hanessian, S.; Yang, H.; Schaum, R. J. Am. Chem. Soc. 1996, 118,
2507–2508.
(21) Weygand, F.; Frauendorfer, E. Chem. Ber. 1970, 103, 2437–2449.
8702 J. Org. Chem. Vol. 73, No. 22, 2008

ꢀ-Amino Alkylzinc Iodides DeriVed from Amino Acids
SCHEME 10. Possible Mechanisms for the First-Order
Elimination of Weinreb Amide Containing ꢀ-Amino
Alkylzinc Iodides
SCHEME 12. Addition of Organometallic Reagents to
Weinreb Amide 49e
SCHEME 11. Cross-Coupling of Zinc Reagents 47 and 48
In this case, the Grignard reagent acted as a base, promoting
decomposition of the Weinreb amide via elimination of the
methoxy group. This mode of reactivity of Weinreb amides has
been reported.24
Conclusions. The counter-intuitive hypothesis that the rate
of elimination of ꢀ-amino alkylzinc iodides can be reduced by
introducing a more electron-withdrawing nitrogen protecting
group has been validated. Furthermore, the observation that
replacement of a Boc group with a TFA group changes the
mechanism of the elimination reaction provides direct evidence
that the interaction of the carbonyl group with zinc is pivotal
in the elimination process. Kinetic analysis of the Negishi cross-
coupling of iodobenzene with ꢀ-amino alkylzinc iodides, derived
from aspartic and glutamic acids, has shown that the nature of
the nitrogen protecting group has only a marginal effect on the
overall rate, and that the main factor that determines reactivity
is the proximity of the ester group. From a synthetic point of
view, the results suggest that the TFA group is an excellent
choice for protection of nitrogen in ꢀ-amino alkylzinc iodides,
since the precursor iodides are stable with respect to oxazoline
formation, without adversely affecting the stability or reactivity
of the alkylzinc iodide.
TABLE 7. Isolated Yields from the Negishi Cross-Coupling of
Zinc Reagents 47 and 48 with Substituted Aryl Iodides
aryl Iodide
zinc reagent
product
Ar
yield,a
%
4-MeC6H4I
4-MeOC6H4I
PhI
4-NCC6H4I
1-naphthylI
4-BrC6H4I
4-MeC6H4I
4-MeOC6H4I
PhI
47
47
47
47
47
47
48
48
48
48
48
49a
49b
49c
49d
49e
49f
50a
50b
50c
50g
50h
4-MeC6H4
4-MeOC6H4
Ph
4-NCC6H4
1-naphthyl
4-BrC6H4
4-MeC6H4
4-MeOC6H4
Ph
68
59
56
67
60
53
70
69
77
51
46
2-H2NC6H4I
2-FC6H4I
2-H2NC6H4
2-FC6H4
a All yields are based on the starting alkyl iodide 44 or 45.
Notwithstanding the greater instability of the Weinreb amide
trifluoroacetamide organozinc reagents 47 and 48, Negishi cross-
coupling with a range of substituted iodobenzenes (Scheme 11)
gave the expected products 49 and 50 in moderate but generally
consistent yields (Table 7, Scheme 11). Preparative cross-
coupling of the N-Boc protected Weinreb amide 46 was not
carried out due to its substantially greater instability with respect
to elimination.
Finally, encouraged by a report on the addition of organo-
metallic reagents to N-sulfinyl ꢀ-amino Weinreb amides,23 we
investigated the addition of organometallic reagents to a typical
Weinreb amide cross coupling product, 49e. This intermediate
was treated with representative Grignard reagents and one
organolithium reagent, giving substitution products 51a-d in
good to excellent yield (Scheme 12). Thus, reagent 47 functions
as the synthetic equivalent of the chiral aminoketone synthon
52, illustrating the potential of this method for the synthesis of
ꢀ-amino ketones.
Experimental Section
General Procedure A: Preparation of Zinc Reagents for
Kinetic NMR Experiments in DMF-d7. Zinc dust (0.236 g, 3.6
mmol, 6.0 equiv) was added to a 25 mL round-bottom flask, with
sidearm, containing a rugby ball-shaped stirrer bar. The flask was
flushed with nitrogen and DMF (nondeuterated, 0.75 mL) and
TMSCl (50 µL) were added under nitrogen via syringe. The solution
was observed to effervesce and the mixture was stirred at room
temperature for 5 min, at the fastest speed possible. The zinc was
allowed to settle and the supernatant solution was removed via
syringe, followed by drying of the zinc under vacuum using heating
from a hot air gun. When the flask had cooled, the iodide (0.6 mmol,
1.0 equiv) was added as a solid and the flask flushed again with
nitrogen, followed by the addition of DMF-d7 (0.75 mL) via syringe.
Note: If the iodide is a liquid it is dissolved in DMF-d7 (0.75 mL)
and added to the zinc via syringe. The solution was stirred at the
fastest speed and cooling using a cold water bath was applied at
the onset of an exotherm, which is usually a reliable indication
that the zinc insertion has occurred. Note: If the insertion is slow,
an exotherm may not be observed and the insertion can be followed
by TLC (Et2O). Mesitylene (25 µL, 0.3 mmol) was added, the zinc
Attempted reaction of the Weinreb amide 49e with isopro-
pylmagnesium chloride gave N-methyl amide 53 in 95% yield.
(23) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Z. Org. Lett. 2003, 5,
925–927.
(24) Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31, 6269–6272.
J. Org. Chem. Vol. 73, No. 22, 2008 8703

Rilatt and Jackson
was allowed to settle and the supernatant transferred via syringe to
a nitrogen-filled NMR tube fitted with a Young’s tap. Reference
used for DMF-d7 (δH 2.74, δC 162.70).
pressure and the crude oil dissolved in CH2Cl2 (5 mL) and
partitioned between diethyl ether (60 mL) and water (20 mL). The
organic phase was washed with brine (10 mL), dried (MgSO4),
filtered, and evaporated under reduced pressure to give the crude
product.
General Procedure B: Preparation of Zinc Reagents and
Monitoring of Cross-Coupling Reaction by NMR Spectroscopy
in DMF-d7. General procedure A is followed until completion of
the zinc insertion. At this point, mesitylene (25 µL), the electrophile
(0.78 mmol, 1.3 equiv), and finely ground P(o-tol)3 and Pd2(dba)3
were added, and the solution was stirred for 1 min. Note: the P(o-
tol)3 was ground in a vial using a spatula before weighing. This
aids dissolution. The zinc was allowed to settle and the supernatant
transferred via syringe to a nitrogen-filled NMR tube fitted with a
Young’s tap. At the completion of the reaction, the mixture was
worked up using procedure C.
General Procedure C: Palladium-Catalyzed Cross-Coupling
of Electrophiles with Organozinc Reagents. Alkyl iodide (0.6
mmol, 1.0 equiv) was weighed into a vial and placed under high
vacuum during the Zn activation period. A 25 mL round-bottom
flask with sidearm, containing a rugby ball-shaped stirrer bar was
removed from the oven and zinc dust added (0.236 g, 3.6 mmol,
6.0 equiv). The flask was flushed with nitrogen and dry DMF (0.75
mL) and TMSCl (100 µL, 0.8 mmol) were added under nitrogen
via syringe. The solution was observed to effervesce and the mixture
was stirred at room temperature for 5 min, at the fastest speed (note:
the DMF occasionally changes to a yellow color during this period).
The zinc was allowed to settle and the supernatant solution was
removed via syringe, followed by drying of the zinc under vacuum
using heating from a hot air gun. The iodide was dissolved in DMF
(0.75 mL) under nitrogen and transferred to the zinc via syringe.
The solution was stirred at 0 °C and the insertion judged by TLC
(dichloromethane) to be complete within 5 min. Tris(dibenzylide-
neacetone)dipalladium (17.9 mg, 0.02 mmol, 2.5 mol % cf.
electrophile), tri-o-tolylphosphine (23.8 mg, 0.08 mmol, 2 equiv
relative to Pd), and the electrophile (1.3 equiv relative to the iodide)
were added to the flask. The flask was covered in aluminum foil
and stirred overnight. The DMF was evaporated under reduced
General Procedure D: Iodination of Alcohols. Iodine, triph-
enylphosphine, and imidazole were added to dry CH2Cl2 under
nitrogen with stirring (caution: exothermic!). A white precipitate
formed, and the solution turned dark orange. A solution of the
alcohol in the minimum volume of dry CH2Cl2 was added slowly
via syringe, whereupon the solution became lighter orange. The
reaction was usually observed to have gone to completion at this
point and can be checked by TLC. The mixture was filtered, the
filtrate concentrated under reduced pressure, and the residue
dissolved in Et2O. The insoluble material was removed by filtration,
and the filtrate washed with saturated sodium thiosulfate solution
(50 mL), whereupon the orange color disappeared. The organic
phase was washed with brine (20 mL), dried over MgSO4, and
filtered and the solvent evaporated under reduced pressure to give
the crude product.
Acknowledgment. We thank OSI Pharmaceuticals for sup-
port of a Ph.D. studentship (I.R.), the RSC for a Journals Grants,
Dr. B. Taylor and Miss S. Bradshaw for NMR spectra, Drs. N.
Buurma and N. H. Williams for advice on analysis of the kinetic
data, and Dr. P. J. Murray for continued interest in the project
and for very helpful comments on the manuscript.
Supporting Information Available: General experimental
procedures, including procedures for analysis of kinetic data;
experimental procedures and characterization data for all
1
compounds; H and 13C NMR spectra for all isolated com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801754K
8704 J. Org. Chem. Vol. 73, No. 22, 2008