Copper(I) mediated cross-coupling of amino acid derived organozinc reagents with acid chlorides

Article abstract of DOI:10.1039/b601996j

This paper describes the development of a straightforward experimental protocol for copper-mediated cross-coupling of amino acid derived β-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides. The present method uses CuCN·2LiCl as the copper source and for organozinc reagent 1 the methodology appears to be limited to reaction with more stable acid chlorides, providing the desired products in moderate yields. When applied to organozinc reagent 3, however, the protocol is more general and provides the products in good yields in all but one of the cases tested. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b601996j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Copper(I) mediated cross-coupling of amino acid derived organozinc
reagents with acid chlorides
Thomas Hjelmgaard and David Tanner*
Received 10th February 2006, Accepted 8th March 2006
First published as an Advance Article on the web 31st March 2006
DOI: 10.1039/b601996j
This paper describes the development of a straightforward experimental protocol for copper-mediated
cross-coupling of amino acid derived b-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides.
The present method uses CuCN·2LiCl as the copper source and for organozinc reagent 1 the
methodology appears to be limited to reaction with more stable acid chlorides, providing the desired
products in moderate yields. When applied to organozinc reagent 3, however, the protocol is more
general and provides the products in good yields in all but one of the cases tested.
has not been documented, reaction of an analogous L-serine
Introduction
derived organozinc reagent with benzoyl chloride in THF after
transmetallation with CuCN·2LiCl has been reported to give the
coupling product in 71% yield.5
More thorough investigations of organozinc reagent 3 have been
published,6 and Pd(0)-catalysed reaction of this L-glutamic acid
derivative with a range of acid chlorides has been reported to give
coupling products 4b–e in moderate yields (45–52%) while failing
to provide 4f (Scheme 1).6c
Since no method for cross-coupling of organozinc reagent 1
with acid chlorides had been reported previously we decided to
use this reagent as the basis for the present study. Furthermore,
since relatively little work concerning this type of reagent has been
published, we likewise decided to synthesize and test the stability
and reactivity of N-protected b-amido-alkylzinc iodide 5 and b-
amino-alkylzinc iodides 6 and 7 (Scheme 2). To our knowledge,
the generation and use of these reagents has not been reported in
the literature.
In connection with a total synthesis project,1 we recently became
interested in cross-coupling reactions involving acid chlorides and
the two amino acid derived b-amido-alkylzinc iodides 1 and 3 to
give coupling products 2 and 4, respectively (Scheme 1).2 Although
our initial interest was focused on the synthesis of 2a and 4a, we
also tested the generality of our developed methodology on a range
of selected acid chlorides and the results are presented in this
paper, along with a comparison with alternative cross-coupling
techniques.
Scheme 2 Other protected pyroglutamic acid-derived (5) and proline-
derived (6 and 7) organozinc reagents of interest.
Scheme 1 Cross-coupling reactions of b-amido-alkylzinc iodides 1 and
3 with acid chlorides to give derivatives 2 and 4, respectively. Key: (a)
transmetallation, RCOCl.
Results and discussion
Acid chlorides
L-Pyroglutamic acid derived organozinc reagent 1 has pre-
viously been used in Cu(I) mediated reactions with various
electrophiles using either CuBr·DMS or the THF-soluble copper
salt CuCN·2LiCl3 as copper source.4 Thus, reaction of 1 with
propargylic tosylates in DMF,4a 1-iodo alkynes in THF–DMF,4b
and bromoallene in DMF,4c gave the derived products in moderate
yields (49–59%). Although reaction of 1 with an acid chloride
All but one of the required acid chlorides were commercially
available. Synthesis of the last acid chloride, 10, was achieved
in three steps from methyl 2-bromobutyrate in 57% overall yield
(Scheme 3).
Ester 8 was obtained in 87% yield by a Reformatsky reaction
of methyl 2-bromobutyrate with a,a-dichloromethyl methyl ether
in the presence of zinc dust.7 Although this method makes use
of the toxic a,a-dichloromethyl methyl ether, the relative ease and
the good yield of this reaction makes it preferable over the other
reported pathway to 8 in two steps in 78% overall yield starting
Department of Chemistry, Building 201, Technical University of Denmark,
Kemitorvet, DK-2800, Kgs. Lyngby, Denmark. E-mail: dt@kemi.dtu.dk;
Fax: + 45 45 93 39 86; Tel: + 45 45 25 21 88
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Reduction of the acid functionality in N-Boc L-proline with
BH3·DMS in refluxing THF13 provided alcohol 14 in 73% yield
after workup and crystallization. Further conversion into the
desired iodo derivative 15 was effected in 83% yield by reaction
with I2, imidazole and PPh3 in Et2O or CH2Cl2.14 We found that
use of a 2:1 mixture of Et2O–CH2Cl2 as solvent for this reaction
proved to be optimal, giving 15 in 61% overall yield.
Iodide 16 was prepared from commercially available N-benzyl
L-prolinol (Scheme 6). Only 38% yield was obtained; the product
was found to be unstable and was thus used as soon as possible
after isolation.
Scheme 3 Synthesis of acid chloride 10 from methyl 2-bromobutyrate.
Key: (a) Zn, MeOCHCl2, Et2O, D, 87%; (b) 2 M NaOH, D; then HCl,
76%; (c) (COCl)2, DMF (cat.), benzene, rt, 86%.
from commercially available, but expensive, ethyl 2-ethylacrylate.8
Hydrolysis of 8 to 9 was effected in 76% yield by refluxing with
2 M NaOH,8 and 10 was then obtained in 86% yield by reaction
of 9 with oxalyl chloride.8
Scheme 6 Synthesis of iodide 16. Key: (a) I2, imidazole, PPh3, CH2Cl2,
rt, 38%.
Iodide 19, the precursor to organozinc reagent 3, was synthe-
sised as shown in Scheme 7.
Synthesis of proline, glutamic acid and pyroglutamic acid derived
iodides
The synthesis of 12 and 13 as precursors to organozinc reagents 1
and 5, respectively, is shown in Scheme 4.
Scheme 7 Synthesis of iodide 19 from L-glutamic acid. Key: (a) SOCl2,
MeOH, −15 ◦C to rt; (b) Boc2O, Et3N, dioxane–water, two steps, 89%;
(c) N-methyl morpholine, ClCO2Et, THF, −10 ◦C; then NaBH4, MeOH,
THF, 0 ◦C, 64%; (d) I2, imidazole, PPh3, Et2O–CH2Cl2, rt, 85%.
Scheme 4 Synthesis of iodides 12 and 13. Key: (a) SOCl2, MeOH, −15 ◦C
to rt; (b) NaBH4, EtOH, 0 ◦C to rt, two steps, 91%; (c) TsCl, Et3N, DMAP,
CH2Cl2, rt; (d) NaI, MeCN, D, two steps, 94%; (e) Boc2O, NaH, THF,
−20 ◦C to rt, 64%.
Selective monoesterification of L-glutamic acid was achieved
by reaction with SOCl2 in MeOH using a modified literature
procedure.9,15 Concentration of the reaction mixture followed by
reaction with Boc2O in dioxane–water in the presence of Et3N,16
afforded the desired N-protected product 17 in 89% yield for
the two steps. Derivative 17 was then transformed into a mixed
anhydride by reaction with N-methyl morpholine and ClCO2Et
and subsequent reduction with NaBH4 in THF–MeOH gave
the desired alcohol 18 in 64% yield using a modified literature
procedure.17 Synthesis of iodo derivative 19 was completed by
subjecting 18 to our developed conditions I2–imidazole–PPh3 in
Et2O–CH2Cl2 (2 : 1) giving 19 in 85% yield. Overall, the synthesis
of 19 was realized in 4 steps and 48% overall yield from L-glutamic
acid.
L-Pyroglutamic was converted into alcohol 11 by reaction with
SOCl2 in MeOH followed by reduction of the crude methyl ester
with an excess of NaBH4 in EtOH. The overall yield for these two
steps was 91% and this route is based on a modified literature
procedure.9 Iodide 12 was then obtained by tosylation of 11 with
TsCl in the presence of Et3N and DMAP,10 followed by refluxing
a mixture of the crude product and NaI in MeCN11 (94% yield
for the two steps and 86% overall yield from L-pyroglutamic acid).
Iodide 13 was obtained by reaction of 12 with Boc2O using NaH
as base,12 in 64% yield.
Synthesis of iodide 15 (Scheme 5) as precursor to 6 was
achieved in two steps from commercially available N-Boc L-proline
following literature procedures.
With the three b-amido iodides 12, 13 and 19 and the two b-
amino iodides 15 and 16 now available, we proceeded to study the
zinc insertion process.
Subjection of proline and pyroglutamic acid derived iodides to zinc
insertion
As mentioned above, organozinc reagent 1, generated by reaction
of activated zinc dust with the parent iodide 12 in DMF at
Scheme 5 Synthesis of iodide 15. Key: (a) BH3·DMS, THF, rt to reflux,
73%; (b) I2, imidazole, PPh3, Et2O or CH2Cl2, rt, 83%.
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◦
◦C, has earlier been used in Cu(I) mediated reactions with
within one hour at 0 C but H-NMR of the quenched reaction
mixture showed the almost exclusive presence of 23 resulting from
b-elimination. This was perhaps not so surprising, since 5 was
expected to be less stable than 1 as a result of the better leaving
group abilities of the amide moiety and better coordinating ability
of the nitrogen protecting group with zinc. The latter effect has
been proposed to be a key parameter in b-elimination from b-
amido-alkylzinc iodides.6c,6f ,22
1
0
various electrophiles in DMF or DMF–THF giving the desired
products in moderate yields.4 An important finding was that 1
was unstable in THF at rt giving rise to substantial amounts
of b-elimination.4a It has previously been reported that dipolar
aprotic solvents such as DMF, DMA, NMP and DMSO stabilize
b-amido zinc reagents,6a and use of DMF as solvent for this zinc
insertion accordingly reduced b-elimination to less than 10%. b-
Elimination was completely eliminated by rinsing the activated
zinc and lowering the temperature to 0 ◦C.4a
We decided to utilize this reported method for zinc insertion as
a basis for the study at hand with one important modification:
DMF has been reported to react with acid chlorides under similar
conditions, a problem which was suppressed by using DMA
instead of DMF.18 Therefore, we decided to make use of these
findings and replace DMF with DMA in our study which was
initially concentrated on organozinc reagents 1 and 5–7.
Not surprisingly, it was found that the quality and mode of
activation of the zinc dust was of major importance for the
insertion reaction. The most reliable results were obtained when
using zinc dust (<10 micron), purchased from Aldrich, after
activation with 1,2-dibromoethane (0.05 equiv.) at 60 ◦C, followed
by TMSCl19 (0.04 equiv.) and sonication20 at rt under N2 in
DMA.3,4a Reaction of the activated zinc with iodides 12, 13, 15
and 16 (Scheme 8) was then followed by TLC. When no starting
material remained the reactions were quenched (with water or
0.1 M HCl) and the crude product compositions were investigated
by 1H-NMR spectroscopy. Thus, if zinc insertion had taken place
and the resulting zinc reagent was stable, one would expect to
isolate the reduced products 20, 21, 24 and 25. If the generated
organozinc intermediate was unstable toward b-elimination, one
would expect the NMR to show the presence of the unsaturated
products 22, 23, 26 and 27.
Similarly, in our hands, the proline derived organozinc reagents
6 and 7, derived from reaction of 15 (in DMA) and 16 (in
DMA–THF 1 : 1), respectively, proved very unstable and only the
elimination products 26 and 27 were present after zinc insertion
and aqueous quench as judged by 1H-NMR. We note that
only a few applications of b-amino-alkylzinc iodides have been
reported,23 and these types of reagents, as well as being prone to
elimination–degradation, also showed reduced reactivity, possibly
due tointra-or inter-molecular complexation between thenitrogen
and the metal center.5,23a
Reaction of pyroglutamic acid derived organozinc reagent with acid
chlorides
We thus concentrated our efforts on organozinc reagent 1 in order
to find the optimal conditions for reaction with acid chlorides,
using benzoyl chloride as standard (Scheme 9).
Scheme 9 Desired product 2b from reaction of 1 with benzoyl chloride
after transmetallating with a copper- or a palladium source. Key: (a) Zn*,
DMA, 0 ◦C; (b) BzCl, copper or palladium transmetallation.
We started with the known organozinc reagent 1. Zinc insertion
in DMA was complete within 2–3.5 hours at 0 ◦C and as
expected, NMR of the crude product after aqueous quench
showed the presence of almost exclusively the reduced product
20†,21 and only traces of 22‡. Unfortunately, none of the three
other cyclic organozinc reagents were found to be stable under
these conditions: zinc insertion into 13 in DMA was complete
Initially, literature procedures for copper-mediated reactions4
involving 1 were directly adapted to our DMA-based system
and the results are listed in Table 1. The DMA solution of the
formed organozinc reagent 1 was first added to a solution of
CuCN·2LiCl (1.0 equiv.) in THF at −40 ◦C. The mixture was
then stirred for 10 minutes at 0 ◦C to ensure formation of the
organocopper reagent. Cooling to −30 ◦C followed by addition of
benzoyl chloride provided the desired product in a moderate 49%
yield after workup (entry 1). Reaction of 1 in DMA at −10 ◦C
with benzoyl chloride in the presence of CuBr·DMS (0.2 equiv.)
was likewise attempted (entry 2) but yielded only traces of the
† Characteristic 1H-NMR signals from the formed CH3-group in 20: d 1.19
(3 H, d, J 6.3).
‡ Characteristic 1H-NMR alkene-signals in 22: d 4.96 (1 H, m, J 10.2),
5.02 (1 H, m, J 17.2) and 5.77 (1 H, m).
Scheme 8 Generation and possible products from aqueous quenching of organozinc reagents 1 and 5–7 derived from 12, 13, 15 and 16. Key: (a) Zn*,
12: DMA, 0 ◦C, 2–3.5 h, 13: DMA, 0 ◦C, 1 h, 15: DMA, −15 ◦C to 0 ◦C, 2 h, 16: DMA–THF 1 : 1, −15 ◦C to −10 ◦C, 1 h; (b) water or 0.1 M HCl.
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Table 1 Results obtained from reaction of 1 with benzoyl chloride yielding 2b under different conditions
Entry
Transmet. agent (equiv.)
Solvent
Temperature
Yield (%)
1
2
3
CuCN·2LiCl (1.0)
CuBr·DMS (0.2)
Pd(PPh3)4 (0.05)
THF–DMA 5 : 1
DMA
Toluene–DMA 5 : 1
−40 ◦C–0 ◦C–−30 ◦
C
49
Trace
0
−10 ◦
C
rt
desired product. For comparison, we included an adaptation of
a literature procedure6c for Pd(0)-catalysed cross-coupling of acid
chlorides with acyclic b-amido-alkylzinc iodides; unfortunately,
this failed completely in our hands (entry 3).
reagent 28 which yields 20 after aqueous workup. Alternatively,
the intermediate deprotonated species could react with benzoyl
chloride giving 2924 which was also observed in smaller amounts.
Our original procedure was somewhat tedious due to the
temperature changes required during the reaction, in combination
with the poor solubility of the reagents during transmetallation.
Thus, formation of a sticky precipitate was observed in the THF–
DMA solvent mixture, which hindered stirring. We therefore
performed some screening experiments, which are summarized
in Table 2.
Based on an early observation that the zinc reagent 1 and/or
copper reagent 28 were soluble in THF–DMA 5 : 1 when warmed
to 0 ◦C, we initially performed the reaction in this solvent
composition, but keeping the temperature at −10 ◦C throughout
the whole reaction (entry 1). Disappointingly, the reagents were
not soluble even at this elevated temperature and furthermore
the yield decreased from 49% to 39%, perhaps indicating that
the reagents were less stable at higher temperatures. Importantly,
though, we proved that the reaction could still provide useful yields
when kept at a constant temperature. Changing the solvent to pure
DMA made a modest improvement in the yield (44%, entry 2)
and eliminated the problems with solubility but revealed another
drawback: the presence of an increased volume of DMA relative to
THF during the reaction resulted in a crude mixture after aqueous
workup that contained substantial amounts of DMA. The result
was a slightly impure product still containing traces of DMA
even after column chromatography. It was eventually found that
concentrating the crude mixture after aqueous workup at ca.
45 ◦C/ca. 2 mmHg removed most of the DMA and the rest
could be removed by adding butyl benzene and concentrating the
resulting mixture at ca. 45 ◦C/ca. 2 mmHg. Column chromatog-
raphy then furnished the pure product and this workup procedure
remained our preferred method.
We thus decided to optimise the conditions for the use
of CuCN·2LiCl as transmetallating agent. When reacted with
organozinc reagents of the type RZnI, CuCN·2LiCl is reported
to give copper reagents tentatively described as RCu(CN)ZnI, but
the exact structures of these reagents remain unknown.2,3 Thus,
for the system at hand, 1 would give a copper species formulated
as 28 which then provides the desired product 2b after reaction
with benzoyl chloride (Scheme 10). As will be discussed below,
a major side product of this reaction was the reduced species
20, presumably formed as a result of slow deprotonation of the
amide functionality by the organozinc reagent 1 and/or copper
Scheme 10 Transmetallation of 1 with CuCN·2LiCl gives a copper
reagent tentatively described as 28 which upon reaction with benzoyl
chloride gives the desired product 2a. Byproducts 20 and 29 presumably
formed as a result of self-quenching of 1 and/or 28 followed by aqueous
quench or reaction with benzoyl chloride. Key: (a) CuCN·2LiCl; (b) BzCl;
(c) quench or BzCl followed by quench.
Table 2 Results obtained from reaction of 1 with benzoyl chloride yielding 2a under different conditions after transmetallating with CuCN·2LiCl
Entry
Solvent
Temperature
2b (%)a
20 (%)b
29 (%)b
c
c
1
2
3
4
5
6
7
8
9
THF–DMA 5 : 1
DMA
−10 ◦
−10 ◦
0 ◦
C
C
C
39
44
29
36
38
52
51
44
—
—
21
51
30
15
14
16
14
6
13
5
4
3
THF–DMA 1 : 1
THF–DMA 1 : 1
THF–DMA 1 : 1
THF–DMA 1 : 1
THF–DMA 1 : 1
THF–DMA 1 : 1
THF–DMA 2 : 1
THF–DMA 3 : 1
Toluene–DMA 1 : 1
THF–DMSO 1 : 1
−10 ◦C
−15 ◦
−25 ◦
−30 ◦
−40 ◦
−25 ◦
−25 ◦
−25 ◦
C
C
C
C
C
C
C
5
3
d
d
d
—
—
—
—
—
—
d
d
d
10
11
12
49
0
15
—
3
−10 ◦C
—
c
c
a Isolated yield after column chromatography. b Calculated yield from 1H-NMR. c Not determined. d 1 and 28 not sufficiently soluble under these
conditions, so further work was abandoned.
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From these two experiments, it seemed that keeping the
temperature constant during the reaction and use of an increased
volume of DMA relative to THF could improve the reaction at
hand. However, it also seemed that elevated temperatures (−10 ◦C)
resulted in lower yields and, since pure DMA freezes at −20 ◦C, a
compromise was needed. THF–DMA 1 : 1 (entries 3–8) proved to
be the solvent composition of choice. The reagents were still not
completely soluble in this solvent mixture, but the reaction mixture
remained an easily stirrable suspension. After having performed
the reaction at a range of different temperatures (entries 3–8) we
found the optimum temperature to be −25 ◦C which gave the
desired product 2a in 52% yield (entry 6). Above this temperature
(entries 3–5) the decrease in yield is probably a result of the lower
thermal stability of zinc reagent 1 and/or copper reagent 28. This
is supported by the substantial increase in the yield of 20 after
Thus, in parallel experiments, iodides 12 and 30 were subjected
to identical conditions during zinc insertion at 0 ◦C and the
reactions were monitored by 1H-NMR. No distinctly measurable
differences between the quenched samples from reaction of 12 and
30 were observed within the time needed for completion of zinc
insertion. This indicated that the organozinc reagents 1 and 31
were stable with respect to self-quench under the conditions used
for zinc insertion. When performing transmetallation of deutero-
species 31 with CuCN·2LiCl and further reaction with benzoyl
chloride following the optimized method in DMA–THF 1 : 1
at −25 ◦C (Scheme 12), we subsequently obtained the desired
product 2b in an almost unchanged 48% yield (relative to 52%
yield, Table 2, entry 6).
◦
“self-quenching” from around 15% (entries 5–8) at −15 C and
below to 30% at −10 ◦C (entry 4) and 51% at 0 ◦C (entry 3).
Furthermore, the yield of 29 also increased from around 4% when
performing the reaction at −10 ◦C or below (entries 3–7) to 13% at
0 ◦C (entry 2). Interestingly, it was found that less 20 was formed
at −10 ◦C in DMA (21%, entry 1) than in THF–DMA 1 : 1 (30%,
entry 3) indicating that the presence of THF may in fact cause a
decrease in the stability of organozinc reagent 1 and/or copper
reagent 28. Below −25 ◦C, the decrease in yield may be explained
by the reduced reactivity of 28 and/or that transmetallation is too
slow.
Interestingly, toluene could be used instead of THF, with
comparable yields (entry 11). Furthermore, organozinc reagent
1 could be formed in DMSO at rt (complete within ca. 2 hours),5
but when further reaction was attempted in THF–DMSO 1 : 1
(entry 12) none of the desired product was obtained.
Overall, the results of these screening experiments did not lead
to any real improvement in yield relative to the initial procedure
(52%, Table 2, entry 6 vs. 49%, Table 1, entry 1) but, importantly,
resulted in a more convenient experimental protocol.
With a convenient experimental procedure at hand, we then
tested the generality of the method by reacting copper reagent 28
with a variety of acid chlorides (Scheme 13, Table 3).
In order to test the hypothesis that the reduced species 20 is
formed by slow deprotonation of the amide functionality by the
organozinc reagent 1 and/or copper reagent 28 (Scheme 10) we
decided to synthesize the deuterated iodide 30 (Scheme 11) and
subject this to the zinc insertion procedure to yield 31. If any self-
quenching would occur one would expect to isolate the deutero-
species 32 along with, or instead of, 20.
Scheme 12 Transmetallation of organozinc reagent 31 with CuCN·2LiCl
to give 33 and further reaction with benzoyl chloride yielding the desired
product 2a along with byproducts 32 and 34 presumably as a result
self-quenching of 31 and/or 33. Key: (a) CuCN·2LiCl, DMA–THF 1 :
1, −25 ◦C; (b) BzCl, DMA–THF 1 : 1, −25 ◦C to rt, 2a: 48%; (c) quench
or BzCl followed by quench.
Interestingly, however, a substantial amount of deuterium
insertion into the reduced product was observed in 1H-NMR of the
crude mixture obtained after aqueous workup. Thus, the reduced
products 20 and 32 were formed in an approximately 1 : 1 mixture
in 16% overall yield. These products could be easily recognized
by the difference in the appearance of characteristic signals in 1H-
NMR from the CH3-group in 20 and the CH2D-group in 32§.
Thus, under the conditions used for transmetallation and further
reaction with benzoyl chloride a slow deprotonation of the amide
functionality in 31 and/or 33 yielding 32 is observed. Analogously,
the byproducts 29 and 34 were observed in a ca. 1 : 1 relationship,
again readily apparent from the characteristic signals in their 1H-
NMR spectra. Since we do not know whether full transmetallation
has taken place under the experimental conditions used, we do not
know if these products derive from 31, 33, or both.
Disappointingly, this cross-coupling technique appears to work
only for relatively stable acid chlorides (Table 3, entries 1, 2 and 5),
providing the desired products in moderate yields at best. When
more reactive acid chlorides were used (entries 3, 4 and 6) none of
the desired products were obtained and NMR spectroscopy of the
crude mixtures after aqueous workup showed only the presence of
reduced product 20 and products resulting from b-elimination.
Scheme 11 Synthesis of deuterated iodide 30 followed by zinc insertion.
Key: (a) D2O, CH2Cl2, rt, 95%; (b) Zn*, DMA, 0 ◦C; (c) quench.
§ 20: d 1.19 (3 H, d, J 6.3); 32: d 1.17 (2 H, dt, J 1.9 and 6.3).
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Table 3 Results obtained from reaction of copper reagent 28 with a
selection of acid chlorides using the developed methodology
Entry
RCOCl
Product
Yield (%)
=
1
2
3
4
5
6
C( CHOCH3)CH2CH3
Ph
2a
2b
2c
2d
2e
2f
51a
52
0
0
44
0
=
CH CH2
CH2OAc
2-Furyl
(CH2)4CH3
a Calculated from NMR.
Scheme 14 Reaction of copper reagent tentatively described as 35, derived
from organozinc reagent 3, with a selection of acid chlorides using the
developed methodology. Key: (a) Zn*, DMA, 0 ◦C; (b) CuCN·2LiCl,
DMA–THF 1 : 1, −25 ◦C; (c) RCOCl, DMA–THF 1 : 1, −25 ◦C to rt.
See Table 4 for yields.
aqueous workup showed only the presence of products from
elimination degradation, 36 and 37 (Scheme 15), and traces of
hydrolyzed organozinc reagent 38.
Scheme 13 Reaction of copper reagent 28 with a selection of acid
chlorides using the developed methodology. Key: (a) Zn*, DMA, 0 ◦C;
(b) CuCN·2LiCl, DMA–THF 1 : 1, −25 ◦C; (c) RCOCl, DMA–THF 1 :
1, −25 ◦C to rt. See Table 3 for yields.
Reaction of glutamic acid derived organozinc reagent with acid
chlorides
As mentioned above, the acyclic L-glutamic acid derived organo-
zinc reagent 3 has previously been used in Pd(0)-catalyzed
reactions with acid chlorides, giving 4b–e in moderate yields (45–
52%) but failing to provide 4f (Scheme 1).6c
When we applied our optimized method to organozinc reagent
3, we were satisfied to find that this technique is generally
applicable to cross-coupling with a range of acid chlorides
(Scheme 14). For this system, organozinc reagent 3 would give
a copper species formulated as 35, and the cross-coupling results
are listed in Table 4, where they are compared to the yields reported
from use of palladium catalysis.6c
As seen in Table 4 the organocopper methodology provided
the desired products in good yields (65–78%, entries 1–2 and
4–6) apart from when acryloyl chloride was used; in this case
none of the desired product was obtained (entry 3). NMR
spectroscopic investigation of the crude reaction mixture after
Scheme 15 Observed byproducts from elimination degradation (36 and
37) and quench (38) of 3 and/or 35. Key: (a) CuCN·2LiCl, DMA–THF
1 : 1, −25 ◦C; (b) b-elimination then quench; (c) quench.
In most cases, only traces of the hydrolyzed organozinc reagent
38 were observed in the NMR of the crude products, indicating
that 3 and 35 were more stable under the reaction conditions
than the cyclic analogs 1 and 28 (Scheme 10). When compared
to the results obtained when palladium catalysis was employed,
our method provided 4f (entry 6) which the palladium catalysis
was unable to, and vice versa for 4c (entry 3). Satisfyingly, the
present methodology provided 4b, 4d and 4e in yields superior
to those reported for the palladium-catalyzed process (13–33%,
entries 2 and 4–5). The results shown in Table 4 thus suggest
that our cross-coupling technique, despite using a stoichiometric
amount of copper, could provide a useful alternative in cases when
the Pd(0)-catalyzed method fails or gives unsatisfactory yields.
Table 4 Results obtained from reaction of copper reagent 35 with a
selection of acid chlorides using the developed methodology
Entry RCOCl
Product Yield (%) Lit. yield (%)a
Conclusion
=
1
2
3
4
5
6
C( CHOCH3)CH2CH3 4a
68
75
0
65
78
77
—
51
48
52
45
0
Ph
4b
4c
4d
4e
4f
We have developed a straightforward experimental protocol for
copper-mediated cross-coupling of organozinc iodides 1 and 3
with a range of acid chlorides (Scheme 1). Our method uses
CuCN·2LiCl as the copper source and for organozinc reagent 1 the
methodology appears to be limited to reaction with more stable
acid chlorides, providing the desired products in moderate yields.
=
CH CH2
CH2OAc
2-furyl
(CH2)4CH3
a Yields reported in the literature utilizing Pd-catalysis.6c
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When applied to organozinc reagent 3, however, the protocol
is more general and provides the products in good yields in all
but one of the cases tested. We consider the latter results to
provide a valuable complement to an existing palladium-catalyzed
protocol,6c delivering amino acid derivatives which are useful
building blocks for construction of modified peptides.6c
3 M HCl. The resulting suspension was filtered and the solid was
washed with a small amount of cold water. Drying the solids in
vacuo yielded 9 (4.46 g, 71%) as a colorless solid. The filtrate was
extracted with Et2O (3 × 40 cm3), and the combined organic phases
were dried over MgSO4, filtered, concentrated and dried in vacuo
yielding crude 9 (0.64 g) as a yellowish solid. This crude product
was crystallized from water (22 cm3) to give further pure 9 (0.29 g,
◦
5%) as a colorless solid: mp 89.0–92.0 C (lit.,8 89.6–90.2 ◦C);
Experimental
NMR spectra were in full accordance with those reported in the
literature.8
General experimental methods
(E)-2-Methoxymethylene-butyryl chloride (10). Oxalyl chlo-
ride (6.55 cm3, 75.1 mmol) was added dropwise to a solution of 9
(8.70 g, 62.5 mmol) and DMF (0.02 cm3, 0.26 mmol) in benzene
(45 cm3) at rt under N2. The mixture was stirred for 2 h and was
then concentrated. Distillation in vacuo gave crude 10 (8.34 g) as a
colorless oil. Re-distillation in vacuo gave pure 10 (7.95 g, 86%) as
a colorless oil: bp 58–59 ◦C/2.0 mmHg and 65–67 ◦C/3.5 mmHg
(lit.,8 58 ◦C/1.2 mmHg); NMR spectra were in full accordance
with those reported in the literature.8
Et2O, THF and toluene were distilled under N2 from sodium–
benzophenone. CH2Cl2 and Et3N were distilled under N2 from
CaH2. Benzene, 1,2-dibromoethane, DMA, DMF, DMSO, EtOH,
˚
MeCN, MeOH and N-methyl morpholine were dried over 4 A
MS. Zn dust (<10 micron) was purchased from Aldrich and was
˚
used as received. Ethyl chloroformate was distilled over 4 A MS
˚
and stored over 4 A MS. All other solvents and chemicals obtained
from commercial source were used without further purification
unless otherwise stated.
Melting points are uncorrected. Specific rotations were mea-
sured on a Perkin Elmer 241 polarimeter using a 10 cm cell and
are given in units of 10−1 deg cm2 g−1. IR spectra were recorded
on a Perkin Elmer 1600 Series FTIR. NMR spectra were recorded
on a Varian Mercury 300 MHz spectrometer. Chemical shifts are
referenced to the residual solvent peak and J values are given in Hz.
Where applicable, assignments were based on DEPT and COSY-
experiments. TLC was performed on Merck TLC aluminum
sheets, silica gel 60, F254. Reactions were, when applicable, followed
by NMR and/or TLC. Visualizing of spots was effected with UV-
light and/or ninhydrin in BuOH–AcOH. Flash chromatography
was performed with silica gel 60, 0.035–0.070 mm, Amicon 85040.
Unless otherwise stated, flash chromatography was performed in
the eluent system for which the Rf-values are given.
(S)-5-Hydroxymethyl-pyrrolidin-2-one (11). To a solution of
L-pyroglutamic acid (14.2 g, 110 mmol) in MeOH (350 cm3) at
−15 ◦C under N2 was added SOCl2 (9.60 cm3, 132 mmol) dropwise.
◦
After stirring for 30 min further at −15 C the reaction mixture
was allowed to warm to rt over 1 h and stirring was continued at
rt for 1 h. The solvent was then removed and the residue was dried
in vacuo. The residue was dissolve◦d in EtOH (350 cm3) under N2
and the mixture was cooled to 0 C. To the solution was slowly
added NaBH4 (8.32 g, 220 mmol). The reaction mixture was then
allowed to heat to rt slowly overnight (stirred for 18 h). Acetic acid
(15.0 cm3, 262 mmol) was added dropwise and the mixture was
stirred for 30 min further at rt under N2. The mixture was then
filtered twice, using the same filter and then twice using a glass fiber
filter until the filtrate was nearly clear. Silica gel (17.5 g) was added
to the filtrate and the resulting mixture was concentrated and dried
in vacuo. The silica gel mixture was added to the top of a short
silica gel column and the product was eluted with EtOAc–MeOH
4 : 1, yielding 11 (11.5 g, 91%) as a colorless solid: Rf (EtOAc–
Elemental analyses were determined at Mikroanalytisches Lab-
oratorium at Institut fu¨r Physikalische Chemie, Universita¨t Wien,
Austria. HRMS were recorded at the Department of Chemistry,
University of Copenhagen, Denmark.
◦
◦
MeOH 4 : 1) = 0.28; mp 71–73 C (lit.,25 72–73 C); [a]D20 +30.5
(c 1.00, EtOH) (lit.,25 [a]D20 +32.4 (c 1.76, EtOH)); NMR spectra
were in full accordance with those reported in the literature.9
(E)-2-Methoxymethylene-butyric acid methyl ester (8). A small
amount (5 cm3) of a mixture of a,a-dichloromethyl methyl ether
(5.00 cm3, 55.3 mmol) and methyl 2-bromobutyrate (13.0 cm3,
113 mmol) in Et2O (50 cm3) was added to a suspension of Zn dust
(14.5 g, 222 mmol) in Et2O (50 cm3) at rt under N2. A catalytic
amount of 1,2-dibromoethane (0.3 cm3) was then added to initiate
the reaction. The rest of the reagent solution was then added over
a period of 1 h while ensuring gentle reflux. After completion
of addition, the reaction mixture was refluxed for 20 min. The
reaction mixture was allowed to cool to rt, filtered, washed with
3% acetic acid (50 cm3) and cold water (2 × 50 cm3), dried over
MgSO4, filtered and concentrated. Flash chromatography of the
residue yielded 8 (6.96 g, 87%) as a colorless oil: Rf (hexane–EtOAc
12 : 1) = 0.28; bp 62–63 ◦C/5 mmHg (lit.,8 58–65 ◦C/1 mmHg);
NMR spectra were in full accordance with those reported in the
literature.8
(S)-5-Iodomethyl-pyrrolidin-2-one (12). To a solution of 11
(2.00 g, 17.4 mmol) and TsCl (3.97 g, 20.8 mmol) in CH2Cl2
(60 cm3) at rt under N2 were added Et3N (4.80 cm3, 34.4 mmol)
and DMAP (212 mg, 1.74 mmol). The mixture was then stirred
for 17 h at rt. The reaction mixture was diluted with CH2Cl2
(40 cm3), poured into water (100 cm3) and acidified with conc.
HCl (2.0 cm3). The organic phase was isolated and the aqueous
phase was extracted with CH2Cl2 (2 × 20 cm3). The combined
organic phases were dried over MgSO4, filtered, concentrated and
dried in vacuo to give the crude tosylate (4.97 g) as a pale yellowish
solid. The crude product was dissolved in MeCN (100 cm3) at rt
under N2 and NaI (7.81 g, 52.1 mmol) was added. The solution was
then refluxed for 4 h under N2. After cooling to rt and filtration,
the solution was concentrated and dried in vacuo (brown solid),
acidified with 1 M HCl (30 cm3) and extracted with CHCl3 (8 ×
60 cm3). The combined organic phases were shaken with 10%
aq. Na2S2O3 (50 cm3) until the brownish color disappeared. The
(E)-2-Methoxymethylene-butyric acid (9). A mixture of 8
(6.93 g, 48.0 mmol) in 2 M NaOH (36.0 cm3, 72.0 mmol NaOH)
was refluxed for 3 h. After cooling to rt, the reaction mixture
was washed with Et2O (20 cm3) and acidified to pH 3–4 with
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(c 1.02, MeOH) (lit.,13 [a]D20 −50.37 (c 1.1, MeOH)); NMR spectra
organic phase was isolated and the aqueous phase was extracted
with CHCl3 (2 × 100 cm3). To the combined organic phases was
added silica gel (5.00 g) and the suspension was concentrated and
dried in vacuo. The silica gel mixture was added to the top of a
short silica gel column and the product was eluted using EtOAc,
yielding 12 (3.66 g, 94%) as a colorless solid: Rf (EtOAc) = 0.33;
were in full accordance with those reported in the literature.13
(S)-2-Iodomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(15). To a suspension of imidazole (1.35 g, 19.8 mmol) a◦nd
triphenylphosphine (3.92 g, 14.9 mmol) in Et2O (24 cm3) at 0 C
under N2 was added iodine (3.78 g, 14.9 mmol) in three portions
over 30 min. A red-brownish solid was formed. After stirring for an
additional 10 min at rt, a solution of 14 (2.00 g, 9.94 mmol) in Et2O
(12 cm3) was added. The red-brownish solid did not dissolve, so
CH2Cl2 (15 cm3) was added and the resulting mixture was stirred
for 16 h at rt. The reaction mixture was then filtered, concentrated
and dried in vacuo and flash chromatography of the residue yielded
15 (2.57 g, 83%) as a colorless solid: Rf (hexane–EtOAc 6 : 1) =
◦
◦
mp 79.5–81.5 C (lit.,11 81 C); [a]D20 −63.6 (c 1.07, EtOH) (lit.,11
[a]2D0 −63 (c 1.24, EtOH)); NMR spectra were in full accordance
with those reported in the literature.11
(S)-2-Iodomethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl
ester (13). NaH (60% in oil, 800 mg, 20.0 mmol) was washed with
hexane (3 × 5 cm3) under N2 and dried in vacuo. THF (10.0 cm3)
was added and the suspension was cooled to −20 ◦C whereupon a
solution of 12 (2.25 g, 10.0 mmol) in THF (10.0 cm3) was added.
After gas evolution had ceased, Boc2O (6.55 g, 30.0 mmol) was
added and the reaction mixture was allowed to heat to rt and
stirring was continued for 30 min at rt. The reaction mixture was
diluted with EtOAc (100 cm3), poured into water (50 cm3) and
the organic phase was isolated. The aqueous phase was extracted
with EtOAc (2 × 100 cm3) and the combined organic phases
were concentrated and dried in vacuo. Flash chromatography
of the residue yielded 13 (2.07 g, 64%) as a colorless solid: Rf
◦
◦
0.45; mp 38–41 C (lit.,14 102–104 C (decomp.)); [a]2D0 −33.1
(c 0.98, CHCl3) (lit.,14 [a]D20 −32.8 (c 1.46, CHCl3)); NMR spectra
were in full accordance with those reported in the literature.14
(S)-1-Benzyl-2-iodomethyl-pyrrolidine (16). To a suspension of
imidazole (717 mg, 10.5 mmol) and triphenylphosphine (2.07 g,
7.90 mmol) in CH2Cl2 (13 cm3) at 0 ◦C under N2 was added iodine
(2.00 g, 7.90 mmol) in three portions over 30 min. After stirring
for an additional 10 min at rt, a solution of N-benzyl-L-prolinol
(0.96 cm3, 5.27 mmol) in CH2Cl2 (13 cm3) was added and the
resulting mixture was stirred for 2.5 h at rt. The reaction mixture
was concentrated and dried in vacuo and flash chromatography of
the residue yielded 16 (608 mg, 38%) as a yellow oil: Rf (hexane–
EtOAc 6 : 1) = 0.45; [a]D20 −22.1 (c 1.26, CHCl3); mmax(neat)/cm−1
3026m, 2939s, 2796s, 1453m, 1347m, 1124s, 740s, 698s, 682s; dH
(300 MHz; CDCl3) 1.57–1.75 (2 H, m), 1.79–1.95 (1 H, m), 2.12–
2.30 (2 H, m), 2.52 (1 H, m), 2.78 (1 H, br d, J 11.3), 3.05 (1 H,
br d, J 11.3), 3.49 (1 H, d, J 13.3), 3.57 (1 H, d, J 13.3), 4.22–4.34
(1 H, m), 7.21–7.36 (5H, m); dC (75.4 MHz; CDCl3) 27.1, 27.3,
37.5, 52.9, 62.5, 63.6, 127.1, 128.2 (2 C), 128.9 (2 C), 137.9. The
product was unstable, and no satisfactory elemental analysis could
be obtained.
◦
(hexane–EtOAc 4 : 1) = 0.28; mp 80.5–82.5 C; [a]2D0 −70.1 (c
1.00, EtOH) (lit.,26 for enantiomer: [a]2D0 +68.4 (c 1.14, EtOH));
Found: C, 36.89; H, 4.85; N, 4.27. C10H16INO3 requires C, 36.94;
H, 4.96; N, 4.31%; mmax(KBr)/cm−1 2976w, 1773s, 1287m, 1153m;
dH (300 MHz; CDCl3) 1.54 (9 H, s), 1.96 (1 H, m), 2.20 (1 H, m),
2.45 (1 H, ddd, J 3.7, 10.8 and 18.0), 2.69 (1 H, ddd, J 9.8, 9.8
and 18.0), 3.39 (1 H, dd, J 8.0 and 10.0), 3.50 (1 H, dd, J 2.6 and
10.0), 4.22 (1 H, m); dC (75.4 MHz; CDCl3) 9.2, 23.1, 28.0 (3 C),
31.1, 57.9, 83.6, 149.6, 173.6.
(S)-1-Deutero-5-iodomethyl-pyrrolidin-2-one (30). To a solu-
tion of 12 (1.13 g, 5.50 mmol) in CH2Cl2 (30 cm3) at rt under N2
was added D2O (3.0 cm3). The mixture was stirred vigorously for
30 min, whereupon the phases were allowed to separate and the
aqueous phase was removed via syringe. D2O (3.0 cm3) was then
added and the mixture was stirred vigorously for another 30 min
before the phases were allowed to separate and the aqueous phase
was removed via syringe. The solution was then concentrated and
dried in vacuo, yielding 30 (1.08 g, 95%) as a colorless solid: Rf
(EtOAc) = 0.33; mp 83–84.5 ◦C; [a]2D0 −63.0 (c 0.99, EtOH); Found:
C, 26.42; H, 3.46; N, 5.93. C5H7DINO requires C, 26.57; H, 3.57;
N, 6.20%; mmax(KBr)/cm−1 2976w, 1686s, 1404w, 1340w, 1288w,
1206w; dH (300 MHz; CDCl3) 1.74–1.92 (1 H, m), 2.28–2.55 (3 H,
m), 3.19 (1 H, dd, J 6.5 and 10.1), 3.24 (1 H, dd, J 5.7 and 10.1),
3.86 (1 H, m); dC (75.4 MHz; CDCl3) 11.1, 27.4, 30.2, 55.0, 177.5.
(S)-2-tert-Butoxycarbonylamino-pentanedioic acid 5-methyl es-
ter (17). To a solution ◦of L-glutamic acid (2.21 g, 15.0 mmol) in
MeOH (50 cm3) at −15 C under N2 was added SOCl2 (1.30 cm3,
18.0 mmol) dropwise. After stirring for 30 min further at −15 ◦C
the reaction mixture was allowed to heat to rt over 1 h and stirring
was continued for 1 h at rt. The mixture was then concentrated and
dried in vacuo. The residue was dissolved in dioxane–water 2 : 1
(60 cm3) at 0 ◦C and Et3N (3.5 cm3, 25.1 mmol followed by 2.0 cm3,
14.3 mmol after 2 h, in all 39.4 mmol) was added until pH = 9–10.
Boc2O (3.70 g, 17.0 mmol) was added and the reaction mixture
was stirred at rt for 3 h. The dioxane was removed in vacuo and
the reaction mixture was diluted with water (20 cm3) whereupon
Na2CO3 (0.30 g, 2.8 mmol) was added in order to keep the solution
basic. The mixture was then washed with Et2O (3 × 10 cm3) and
acidified to pH ∼2 with conc. HCl (2.0 cm3). The product was
extracted with Et2O (4 × 40 cm3) and the combined organic phases
were washed with brine (20 cm3), dried over MgSO4, filtered,
concentrated and dried in vacuo yielding 17 (3.47 g, 89%) as a
colorless oil: Rf (MeOH) = 0.64; [a]2D0 +16.5 (c 1.40, CHCl3) (lit.,16
[a]D +17.15 (c 1.53, CHCl3)); NMR spectra were in full accordance
with those reported in the literature.16
(S)-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl es-
ter (14). N-Boc L-proline (5.50 g, 25.6 mmol) was dissolved
in THF (38 cm3) at rt under N2 and BH3·DMS (95% in DMS,
2.80 cm3, 28.1 mmol) was added dropwise over 30 min. The
reaction mixture was then refluxed for 2 h. After cooling to rt,
ice (20 g) was added and the mixture was extracted with CH2Cl2
(2 × 100 cm3). After filtration through Celite, the solvent was
removed in vacuo giving a crude product (4.99 g) as a colorless
solid. Crystallization from Et2O◦(6 cm3) gave pure 14 (3.73, 73%)
(S) - 4 - tert - Butoxycarbonylamino - 5 - hydroxy - pentanoic acid
methyl ester (18). 17 (3.14 g, 12.0 mmol) was dissolved in THF
◦
as a colorless solid: mp 58–61 C (lit.,13 59–60 C); [a]D20 −53.8
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(60 cm3) under N2 and the solution was cooled to −10 ◦C. N-
Methyl morpholine (1.32 cm3, 12.0 mmol) was added followed
by ethyl chloroformate (1.15 cm3, 12.1 mmol) and the reaction
mixture was stirred for 10 min at −10 ◦C. NaBH4 (1.36 g,
36.0 mmol) was then added followed by slow addition of MeOH
(60 cm3) over a period of 15 min at 0 ◦C. The solution was
stirred for 10 min further and was then neutralized with 1 M
HCl (20 cm3). The organic solvents were removed in vacuo and the
residue was extracted with EtOAc (3 × 100 cm3). The combined
organic phases were washed with 1 M HCl (50 cm3), water (50 cm3),
5% aq. NaHCO3 (50 cm3), water (2 × 50 cm3), dried over Na2SO4,
concentrated and dried in vacuo. Flash chromatography of the
residue yielded 18 (1.89 g, 64%) as a colorless oil: Rf (hexane–
EtOAc 1 : 1) = 0.23; [a]D20 −14.0 (c 1.35, CHCl3) (lit.,16 [a]D −10.48
(c 2.88, CHCl3)); NMR spectra were in full accordance with those
reported in the literature.6b
with EtOAc (3 × 16 cm3). The combined organic extracts were
dried over Na2SO4, filtered and concentrated. In order to remove
most of the residual DMA, the mixture was concentrated further at
ca. 45 ◦C in high vacuum (ca. 2 mmHg). For products derived from
12 further (complete) removal of DMA was necessary: The residue
was suspended in MeOH (1.0 cm3), butyl benzene (5 cm3) was
added and the mixture was concentrated at ca. 45 ◦C/ca. 2 mmHg.
Suspension in MeOH (1.0 cm3) followed by addition of butyl
benzene (5 cm3) and concentration at ca. 45 ◦C/ca. 2 mmHg was
repeated twice more. The residue was then suspended in MeOH
(10 cm3) and the mixture was filtered, concentrated and dried in
vacuo.
(S)-5-[(E)-3-(Methoxymethylene)-2-oxopentyl]-pyrrolidin-2-one
(2a). Reaction of 12 (180 mg, 0.800 mmol) with 10 (119 mg,
0.801 mmol) following the general procedure followed by
flash chromatography of the residue yielded 2a (90 mg, 53%)
as a yellowish oil containing 4.0% wt./8.7 mol% hydrolyzed
zinc-reagent 20 as judged by NMR. Thus, the effective yield of
2a was 86 mg, 51%. 2a: Rf (EtOAc–MeOH 10 : 1) = 0.25; Rf
(CH2Cl2–MeOH 20 : 1) = 0.26; [a]2D0 +27.6 (c 0.99, CH2Cl2);
mmax(neat)/cm−1 3354m, 2968m, 1692s, 1634s, 1462m, 1320m,
1250s, 1147m, 1084m, 1012m, 990m; dH (300 MHz; CDCl3) 0.91
(3 H, t, J 7.5), 1.60–1.80 (1 H, m), 2.22 (2 H, q, J 7.5), 2.25–2.38
(3 H, m), 2.63 (1 H, dd, J 9.4 and 16.8), 2.82 (1 H, dd, J 3.8 and
16.8), 3.87 (3 H, s), 4.05 (1 H, m), 6.23 (1 H, br s), 7.18 (1 H, s);
dC (75.4 MHz; CDCl3) 13.2 (CH3), 16.2 (CH2), 26.8 (CH2), 29.6
(CH2), 43.9 (CH2), 50.4 (CH), 61.6 (CH3), 123.6 (C), 160.2 (CH),
177.5 (C), 196.9 (C). This material was not further characterised.
(S)-4-tert-Butoxycarbonylamino-5-iodo-pentanoic acid methyl
ester (19). To a suspension of imidazole (908 mg, 13.3 mmol)
and triphenylphosphine (2.63 g, 10.0 mmol) in Et2O–CH2Cl2 2 : 1
(20 cm3) at 0 ◦C under N2 was added iodine (2.54 g, 10.0 mmol) in
three portions over 30 min; a yellow–gray solid was formed. After
stirring for an additional 10 min at rt, a solution of 18 (1.65 g,
6.67 mmol) in Et2O–CH2Cl2 2 : 1 (10.0 cm3) was added and the
resulting mixture was stirred for 22 h at rt. The reaction mixture
was filtered, the solids were washed with Et2O and the filtrate was
concentrated and dried in vacuo. Flash chromatography of the
residue yielded 19 (2.03 g, 85%) as a colorless solid: Rf (hexane–
EtOAc 4 : 1) = 0.40; mp 91–92 ◦C (lit.,6b 92–93 ◦C); [a]2D0 −12.2 (c
0.98, CH2Cl2) (lit.,6b [a]D −15.6 (c 1.38, CH2Cl2)); NMR spectra
were in full accordance with those reported in the literature.6b
(S)-5-(2-Oxo-2-phenyl-ethyl)-pyrrolidine-2-one (2b). Reaction
of 12 (180 mg, 0.800 mmol) with benzoyl chloride (113 mg,
0.804 mmol) following the general procedure followed by flash
chromatography of the residue yielded 2b (84 mg, 52%) as a
yellowish solid: Rf (EtOAc–MeOH 20 : 1) = 0.43; mp 134–136 ◦C;
[a]2D0 +72.3 (c 0.93, CH2Cl2); Found: C, 70.70; H, 6.51; N, 6.81.
C12H13NO2 requires C, 70.92; H, 6.45; N, 6.89%; mmax(KBr)/cm−1
3187m, 2897w, 1708s, 1684s, 1654m, 1349m, 1334m, 1206m, 758m,
687m; dH (300 MHz; CDCl3) 1.78–1.94 (1 H, m), 2.28–2.52 (3 H,
m), 3.11 (1 H, dd, J 9.4 and 17.9), 3.33 (1 H, dd, J 3.5 and 17.9),
4.14–4.26 (1 H, m), 6.08–6.38 (1 H, br s), 7.44–7.52 (2 H, m),
7.57–7.74 (1 H, m), 7.91–7.97 (2 H, m); dC (75.4 MHz; CDCl3)
26.8 (CH2), 29.7 (CH2), 45.3 (CH2), 50.0 (CH), 127.9 (2 C, CH2),
128.7 (2 C, CH2), 133.6 (CH), 136.1 (C), 177.6 (C), 198.3 (C).
General procedure for generation and reaction of amino acid
derived organozinc reagents with acid chlorides
To a suspension of Zn dust (105 mg, 1.61 mmol) in DMA
(0.40 cm3) at rt under N2 was added 1,2-dibromoethane (0.014 cm3,
◦
0.162 mmol), and the resulting mixture was stirred at 60 C for
10 min. The mixture was cooled to rt and TMSCl (0.016 cm3,
0.127 mmol) was added whereupon the mixture was sonicated for
30 min at rt. The zinc was allowed to settle and the supernatant was
removed via syringe. DMA (0.40 cm3) was added, the solution was
cooled to 0 ◦C and a solution of the iodide (0.80 mmol) in DMA
(0.40 cm3) was added dropwise. The mixture was then stirred at
0
◦C (2.5–3.5 h for 12; 1–2 h for 19) until no starting material
remained as judged by TLC (CHCl3–MeOH 20 : 1 for 12; hexane–
EtOAc 4 : 1 for 19).
(S)-5-(2-Furan-2-yl-2-oxo-ethyl)-pyrrolidine-2-one (2e). Reac-
tion of 12 (180 mg, 0.800 mmol) with 2-furoyl chloride (105 mg,
0.805 mmol) following the general procedure followed by flash
chromatography of the residue yielded 2e (68 mg, 44%) as a
yellowish solid: Rf (EtOAc–MeOH 20 : 1) = 0.26; mp 143–145 ◦C;
[a]2D0 +63.2 (c 0.76, CH2Cl2); Found: C, 61.91; H, 5.77; N, 7.16.
C10H11NO3 requires C, 62.17; H, 5.74; N, 7.25%; mmax(KBr)/cm−1
3246m, 3110w, 1664s, 1637m, 1472m, 1401m, 1288w, 1249w,
1004w; dH (300 MHz; CDCl3) 1.74–1.92 (1 H, m), 2.28–2.48
(3 H, m), 2.97 (1 H, dd, J 9.5 and 17.5), 3.20 (1 H, dd, J 3.7
and 17.5), 4.10–4.21 (1 H, m), 6.04–6.26 (1 H, br s), 6.57 (1 H,
dd, J 1.7 and 3.6), 7.23 (1 H, dd, J 0.7 and 3.6), 7.60 (1 H, dd, J
0.7 and 1.7); dC (75.4 MHz; CDCl3) 26.8 (CH2), 29.9 (CH2), 44.8
(CH2), 49.8 (CH), 112.5 (CH), 117.6 (CH), 146.7 (CH), 152.1 (C),
177.5 (C), 187.2 (C).
LiCl (68 mg, 1.60 mmol) and CuCN (72 mg, 0.804 mmol) were
◦
dried for 5.5 h or overnight at 150 C in vacuo in the flask to be
used for reaction. The mixture was dissolved in THF–DMA 3 : 2
(5.0 cm3) at rt under N2 and the resulting solution was cooled to
−25 ◦C. The DMA-solution of the previously formed organozinc
reagent was then added dropwise, rinsing the residual excess of
zinc with DMA (0.20 cm3), avoiding transferring too much zinc.
The reaction mixture was stirred at −25 ◦C for 10 min whereupon
the freshly distilled acid chloride (0.80 mmol) was added dropwise.
The reaction mixture was stirred at −25 ◦C for 3 h and was then
allowed to heat to rt overnight. The reaction mixture was diluted
with EtOAc (16 cm3) and poured into satd. aq. NH4Cl (8 cm3). The
organic phase was isolated and the aqueous phase was extracted
1804 | Org. Biomol. Chem., 2006, 4, 1796–1805
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(S)-4-tert-Butoxycarbonylamino-(E)-7-methoxymethylene-6-
oxo-nonanoic acid methyl ester (4a). Reaction of 19 (286 mg,
0.801 mmol) with 10 (119 mg, 0.801 mmol) following the general
procedure followed by flash chromatography of the residue yielded
4a (188 mg, 68%) as a colorless oil: Rf (heptane–EtOAc 3 : 2) =
0.33; [a]2D0 −9.0 (c 0.99, CH2Cl2); m/z HRMS (FAB+) Found
[M + H]+ 344.2087. C17H30NO6 requires 344.2073; mmax(neat)/cm−1
3359s, 2976s, 1739s, 1700s, 1633s, 1520s, 1453m, 1366m, 1249s,
1169s; dH (300 MHz; CDCl3) 0.91 (3 H, t, J 7.5), 1.41 (9 H, s),
1.74–1.96 (2 H, m), 2.23 (2 H, q, J 7.5), 2.38 (2 H, t, J 7.4), 2.62 (1
H, dd, J 6.1 and 15.6), 2.87 (1 H, dd, J 4.7 and 15.6), 3.66 (3 H,
s), 3.88 (3 H, s), 3.80–3.90 (1 H, m), 5.16 (1 H, br d, J 8.2), 7.28
(1 H, s); dC (75.4 MHz; CDCl3) 13.2 (CH3), 16.2 (CH2), 28.3 (3 C,
CH3), 29.4 (CH2), 31.1 (CH2), 41.6 (CH2), 48.4 (CH), 51.6 (CH3),
61.6 (CH3), 79.1 (C), 124.1 (C), 155.5 (C), 160.8 (CH), 173.9 (C),
197.6 (C).
(CH2), 31.2 (CH2), 43.2 (CH2), 47.0 (CH), 51.6 (CH3), 79.2 (C),
155.4 (C), 173.7 (C), 210.0 (C).
Acknowledgements
We thank the Technical University of Denmark for financial
support.
References
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3358m, 2956s, 2872m, 1735s, 1717s, 1522m, 1438m, 1366m,
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