Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine

Article abstract of DOI:10.1016/j.tet.2020.131899

The development of suitable reaction conditions for the rapid “high” temperature lithiation-trapping of N-Boc pyrrolidine under batch and flow conditions is described. For optimisation of batch conditions, the lithiation-trapping was explored using s-BuLi at temperatures of ?30 to 20 °C. Two new batch lithiation conditions were discovered using the biomass-derived, sustainable solvent, 2-MeTHF: diamine-free lithiation in 2-MeTHF gave α-substituted pyrrolidines in 50–69% yields at ?20 °C or 0 °C. The requirement for very short lithiation times is explained by the chemical instability of the lithiated intermediate at high temperatures. A practical flow chemistry reaction manifold (s-BuLi, TMEDA, THF, 0 °C, 5 s) has been developed which delivered an α-substituted pyrrolidine in 59% yield. This flow process opens up new opportunities for scaling-up of lithiation-trapping reactions of N-Boc heterocycles.

Full text of DOI:10.1016/j.tet.2020.131899

Tetrahedron 81 (2021) 131899
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rapid “high” temperature batch and flow lithiation-trapping of N-Boc
pyrrolidine*
Alice Kwong, James D. Firth, Thomas J. Farmer, Peter O’Brien*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of suitable reaction conditions for the rapid “high” temperature lithiation-trapping of
N-Boc pyrrolidine under batch and flow conditions is described. For optimisation of batch conditions, the
lithiation-trapping was explored using s-BuLi at temperatures of ꢀ30 to 20 ꢁC. Two new batch lithiation
conditions were discovered using the biomass-derived, sustainable solvent, 2-MeTHF: diamine-free
Received 1 December 2020
Accepted 21 December 2020
Available online 24 December 2020
lithiation in 2-MeTHF gave
a
-substituted pyrrolidines in 50e69% yields at ꢀ20 ꢁC or 0 ꢁC. The require-
Keywords:
Lithiation
Amine synthesis
Flow chemistry
Pyrrolidines
ment for very short lithiation times is explained by the chemical instability of the lithiated intermediate
at high temperatures. A practical flow chemistry reaction manifold (s-BuLi, TMEDA, THF, 0 ꢁC, 5 s) has
been developed which delivered an
new opportunities for scaling-up of lithiation-trapping reactions of N-Boc heterocycles.
© 2021 Elsevier Ltd. All rights reserved.
a-substituted pyrrolidine in 59% yield. This flow process opens up
1. Introduction
to ꢀ68 ꢁC for 2.5e3 h, a not-inconsiderable task and expense given
the scale involved [10].
Heterocycles such as pyrrolidines, piperidines, piperazines and
morpholines are amongst the most common saturated ring systems
in blockbuster drug molecules [1,2]. In this context, there are a
As part of our ongoing work on the synthesis of a-substituted
saturated nitrogen hetoerocycles [11], we have previously reported
a diamine-free, “high” temperature lithiation-trapping protocol for
growing number of marketed pharmaceuticals that contain the
a-
N-Boc pyrrolidine 1 which, using PhCHO, delivered a-trapped
substituted pyrrolidine motif, including the anti-cancer and anti-
viral agents Larotrectinib [3], Acalabrutinib [4] and Telaprevir [5]
(Fig. 1A). The lithiation-trapping of N-Boc heterocycles, first intro-
duced by Beak in 1989 (using s-BuLi/TMEDA in Et2O at ꢀ78 ꢁC) [6],
product 2 (75:25 dr) in 84% yield (Fig. 1B) [12,13]. The lithiation was
accomplished using s-BuLi in THF at ꢀ30 ꢁC for just 5 min. Despite
the improvement on both reaction temperature and lithiation time
compared to Beak’s original report (ꢀ78 ꢁC, 3.5 h, TMEDA required),
we were not entirely satisfied with these reaction conditions and
hypothesised that it might be possible to push the lithiation tem-
perature even higher than ꢀ30 ꢁC. However, our previously re-
ported attempts at this were somewhat discouraging: lithiation of
N-Boc pyrrolidine 1 in THF at ꢀ20 ꢁC for 30 min, ꢀ10 ꢁC for 5 min
is a useful route to a-substituted saturated nitrogen heterocycles
[7] and continues to be exploited in the synthesis of potential drugs
by medicinal and process chemists [5,8,9]. For example, lithiation-
carboxylation of ~100 kg of a bicyclic N-Boc pyrrolidine was carried
out by process chemists at Vertex in the synthesis of the hepatitis C
drug Telaprevir [2]. Similarly, at Merck,
a
lithiation-
and 0 ꢁC for 30 min followed by PhCHO trapping gave
a-substituted
transmetallation-Negishi cross-coupling reaction was carried out
on ~1 kg scale starting from N-Boc pyrrolidine en route to a
glucokinase activator (Fig. 1A) [8]. In both examples, s-BuLi and a
bispidine diamine in tert-butyl methyl ether were used for the
lithiation step and the reaction temperature was maintained at ꢀ75
pyrrolidine 2 in 0e29% yield (Fig. 1B) [12]. We had previously
concluded that these lower yields were due to consumption of
more s-BuLi by a-lithiation of the THF solvent [14], facilitated by the
higher temperatures. On reflection, we began to consider an
alternative explanation, namely that the lithiated N-Boc pyrrolidine
is chemically unstable if left for ꢂ5 min at these higher tempera-
tures. This idea ultimately led us to revisit lithiation temperatures
above ꢀ30 ꢁC, due to the potential energy savings associated with
large-scale (e.g. kg-scale) reactions. Furthermore, we also wished to
fully explore 2-MeTHF as a reaction solvent. The advantages of
using 2-MeTHF are that it is a biomass-derived, sustainable solvent
*
This paper is dedicated with much respect to the memory of Professor Jona-
than M. J. Williams, a wonderfully creative synthetic chemist who was sadly taken
too soon.
* Corresponding author.
E-mail address: peter.obrien@york.ac.uk (P. O’Brien).
https://doi.org/10.1016/j.tet.2020.131899
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

A. Kwong, J.D. Firth, T.J. Farmer et al.
Tetrahedron 81 (2021) 131899
The lithiations were conducted at temperatures ranging
from ꢀ30 ꢁC to 20 ꢁC for ꢃ5 min before trapping with Me3SiCl. The
% yield of silyl pyrrolidine 3 isolated after purification by chroma-
tography was used to compare the efficiencies of the different
conditions. The four sets of lithiation conditions were chosen based
on our previously reported diamine-free, “high” temperature lith-
iations in THF (Fig. 1B) and Beak’s original conditions (Et2O,
TMEDA) [6] as well as the desire to explore analogous reactions in
2-MeTHF (with and without added TMEDA). The full results under a
range of lithiation temperatures and times are presented in Table 1.
Lithiations at ꢀ30 ꢁC for 5 min before reaction with Me3SiCl
delivered silyl pyrrolidine 3 in yields of 66e76% under the four sets
of conditions (entry 1), clearly indicating that all were suitable for
synthetic applications. A similar profile in % yields of 3 was found
at ꢀ20 ꢁC for 5 min (57e71%, entry 2) and at ꢀ20 ꢁC for 2 min
(52e70%, entry 3). In THF or 2-MeTHF at ꢀ20 ꢁC for 2 min, yields of
3 were 65% and 52% respectively (entry 3). However, lower yields of
3
(particularly for the reaction in 2-MeTHF) were obtained
at ꢀ10 ꢁC for 2 min (entry 4). To account for this, as proposed in the
Introduction, we suspected that the generated lithiated N-Boc
pyrrolidine is chemically unstable at temperatures above ꢀ20 ꢁC.
As a result, even shorter lithiation times for reactions at ꢀ10 ꢁC and
above were explored (entries 5e9). For example, lithiating N-Boc
pyrrolidine 1 at ꢀ10 ꢁC for 30 s gave a satisfactory yield profile
(46e74%, entry 6). However, at this high temperature, it was
noticeable that reactions in the presence of TMEDA (69e74%) were
higher yielding than those without TMEDA (46e47%). We ascribe
this to a better chemical stability of the TMEDA-complexed lithi-
ated N-Boc pyrrolidine which is supported by a more detailed study
of chemical stability under different conditions (vide infra). Finally,
lithiation at 0 ꢁC was explored but an extremely short lithiation
time of 5 s was required to obtain synthetically useful yields
(50e63%, entry 8). Lithiations at 0 ꢁC for just 2 s led to disap-
pointing yields of 3 (16e33%, entry 9). Clearly, attempts to push the
reaction temperature as high as possible had reached their limit
and we do not recommend the use of 20 ꢁC for these types of
lithiations.
Next, we explored the chemical stability of the lithiated N-Boc
pyrrolidine at 0 ꢁC using the four sets of conditions. Our plan was to
generate the intermediate organolithium by lithiation of N-Boc
pyrrolidine 1 with 1.3 equiv. of s-BuLi at ꢀ30 ꢁC over 5 min in each
of the four solvent systems (a)-(d) from Table 1. Then, the lithiated
species would be incubated at 0 ꢁC for 5 min or 30 min before
trapping with Me3SiCl to give silyl pyrrolidine 3. The % yield ob-
tained after purification by chromatography would then be used as
a reporter on the chemical stability of the lithiated N-Boc pyrroli-
dine at 0 ꢁC. The results obtained from these incubation experi-
ments are shown in Table 2.
Fig. 1. A. Exemplar pharmacologically active
a-substituted pyrrolidines. B. Previous
work: Diamine-free lithiation-trapping of N-Boc pyrrolidine 1. C. This work: High
yielding lithiation-trapping of N-Boc pyrrolidine 1 at temperatures above ꢀ30 ꢁC and a
flow variant using s-BuLi and TMEDA in THF at 0 ꢁC.
and it is less water-miscible than THF making it preferable to THF
for working-up reactions, especially on scale [15,16]. With both of
these key aspects in mind, we explored the lithiation-trapping of N-
Boc pyrrolidine 1 ate30 ꢁC and above with reactions times of 5 min
or less (batch conditions, Fig. 1C). Ultimately, this led to new “high”
temperature lithiation-trapping conditions (2-MeTHF at ꢀ20 ꢁC or
0
ꢁC) for N-Boc pyrrolidine 1.
As a final aim, having developed a lithiation protocol that
required a very short reaction time (5 s) at 0 ꢁC, we also wished to
explore an increasingly popular method for working with organo-
lithium intermediates that are unstable at “high” temperatures,
namely the use of continuous flow technology. The topical nature of
flow organolithium chemistry is highlighted by the fact that four
excellent review articles, authored by Nagaki [17], Piccardi [18],
Nagaki/Luisi [19] and McGlacken [20], have appeared in the last
two years. Although a wide range of reactions proceeding via
organolithium intermediates have now been carried out using flow
chemistry [17e21], it is notable that this technology has not pre-
viously been applied to a lithiation-trapping reaction of a N-Boc
heterocycle. Herein, we describe both batch and flow lithiation-
trapping of N-Boc pyrrolidine 1 at temperatures above ꢀ30 ꢁC.
The % yields of silyl pyrrolidine 3 obtained by direct trapping
after lithiating at ꢀ30 ꢁC for 5 min in the four different solvent
systems are shown in entries 1, 4, 7 and 10 in Table 2 as points of
reference. In all four conditions, lower yields of silyl pyrrolidine 3
were obtained after incubation at 0 ꢁC for 5 min (compare entries 1/
2, 4/5, 7/8 and 10/11). Furthermore, extending the incubation time
at 0 ꢁC to 30 min led to extremely low or no isolated yields of silyl
pyrrolidine 3 (0e4%, entries, 3, 6, 9 and 12). Taken together, these
results implicate chemical instability of the lithiated N-Boc pyrro-
lidine as the source of low yields under “high” temperature lith-
iation conditions over longer lithiation times. Indeed, this provides
an explanation for the very low yielding results for the lithiation-
trapping of N-Boc pyrrolidine 1 obtained in THF at temperatures
of ꢀ20 ꢁC or above from our earlier study [12] (Fig. 1B).
2. Results and discussion
To start, the lithiation-trapping of N-Boc pyrrolidine 1 was car-
ried out under different reaction conditions. Thus, 1.3 equiv. of s-
BuLi was used to lithiate N-Boc pyrrolidine 1 (1 mmol scale) in four
solvent systems: (a) THF alone, (b) 2-MeTHF alone, (c) 2-MeTHF
with 1.3 equiv. of TMEDA and (d) Et2O with 1.3 equiv. of TMEDA.
The results in Table 2 also highlight two additional points. First,
lithiated N-Boc pyrrolidine appears to be more chemically unstable
in 2-MeTHF than in THF (compare entries 2/5). Second, TMEDA
2

A. Kwong, J.D. Firth, T.J. Farmer et al.
Tetrahedron 81 (2021) 131899
Table 1
Investigation of reaction conditions for the lithiation-trapping of N-Boc pyrrolidine 1 to give silyl pyrrolidine 3.
Entry
Temp (ꢁC)
Time
(a) THF
(b) 2-MeTHF
(c) 2-MeTHF þ TMEDAb
(d) Et2O þ TMEDAb
Yield of 3 (%)a
Yield of 3 (%)a
Yield of 3 (%)a
Yield of 3 (%)a
1
2
3
4
5
6
7
8
9
ꢀ30
ꢀ20
ꢀ20
ꢀ10
ꢀ10
ꢀ10
0
5 min
5 min
2 min
2 min
1 min
30 s
10 s
5 s
2 s
66
64
65
53
58
47
e
69
57
52
28
35
46
31
50
33
76
69
68
e
73
71
70
e
e
67
69
55
53c,d
30
74
e
0
20
59
22
63
16
a
Yield after purification by chromatography.
1.3 equiv. of TMEDA.
The % yield of 3 in Et2O alone was 20%, probably due to a slower rate of lithiation in the absence of TMEDA.
The % yield of 3 in TBME with TMEDA was 67% (14% in absence of TMEDA).
b
c
d
appears to have a minor stabilising effect on the stability of lithiated
N-Boc pyrrolidine (compare entries 5/8). Of note, the use of THF or
Et2O/TMEDA appear to stabilise the lithiated N-Boc pyrrolidine to
the highest degree (entries 2 and 11). Unfortunately, we have not
been able to identify a pathway for the chemical instability of
lithiated N-Boc pyrrolidine. At first, we considered that lithiation of
the solvent by the generated lithiated N-Boc pyrrolidine may be
give a carbene (Table 2), both processes that could be facilitated by
higher temperatures. Disappointingly, despite careful analysis of
the 1H NMR spectra of the crude reaction mixtures and attempted
isolation of any by-products, we have been unable to identify any
products from either of these proposed pathways. For that reason,
these two suggested decomposition pathways must be treated as
speculative at this point.
occurring. For example,
a
-lithiation of THF and 2-MeTHF and
b
-
Based on the results presented in Table 1 and the conclusions
from Table 2, two useful sets of reaction conditions for carrying out
the racemic lithiation-trapping of N-Boc pyrrolidine 1 in 2-MeTHF
can be identified: (i) ꢀ20 ꢁC for 2 min (Table 1, entry 3) and (ii)
0 ꢁC for 5 s (Table 1, entry 8). Using each of these conditions, better
% yields of silyl pyrrolidine 3 were obtained with added TMEDA.
However, even diamine-free lithiation-silylation in 2-MeTHF
delivered useful % yields of approximately 50%. Two other elec-
trophiles (PhCHO and DMF) were explored under our recom-
mended conditions and the results in 2-MeTHF with and without
TMEDA present are summarised in Scheme 1. When using these
reaction conditions in synthetic applications on a small-scale, the
conditions at ꢀ20 ꢁC for 2 min or 0 ꢁC for 5 s will be suitable for
batch reactions.
lithiation-elimination of Et2O by organolithiums are known pro-
cesses [14,22]. However, the lack of formation of significant
amounts of N-Boc pyrrolidine 1 after incubation at 0 ꢁC for 30 min
did not fit with that proposal. Instead, we imagine that lithiated N-
Boc pyrrolidine decomposes either via a retro-[3 þ 2] cycloaddition
(in an analogous way to lithiated THF [14]) or via a-elimination to
Table 2
Investigation of the chemical stability of lithiated N-Boc pyrrolidine.
At this stage, it was clear that these new “high” temperature
conditions were unlikely to be suitable for larger-scale batch re-
actions. Furthermore, given the inherent instability of lithiated N-
Entry
1
2
3
4
5
6
7
8
Solvent)
THF
THF
THF
2-MeTHF
2-MeTHF
2-MeTHF
Time (min)
n.a.
5
30
n.a.
5
30
n.a.
5
Yield of 3 (%)a
66c
51
4
54c
18d
2e
2-MeTHF þ TMEDAb
2-MeTHF þ TMEDAb
2-MeTHF þ TMEDAb
Et2O þ TMEDAb
Et2O þ TMEDAb
Et2O þ TMEDAb
76c
25
2
9
30
n.a.
5
10
11
12
73c
52
0f
30
a
Yield after purification by chromatography.
1.3 equiv. of TMEDA.
This experiment was not incubated at 0 ꢁC; % yield obtained after trapping
b
c
directly after 5 min at ꢀ30 ꢁC.
d
6% of starting material 1 also isolated.
24% of starting material 1 also isolated.
20% of starting material 1 also isolated.
e
f
Scheme 1. Lithiation-trapping of N-Boc pyrrolidine 1 in 2-MeTHF at ꢀ20 ꢁC and 0 ꢁC.
3

A. Kwong, J.D. Firth, T.J. Farmer et al.
Tetrahedron 81 (2021) 131899
Table 3
BuLi/TMEDA) using continuous flow methods and this opens up
new opportunities for these lithiation-trapping processes,
including the potential for scale-up.
Optimisation of continuous flow synthesis of silyl pyrrolidine 3.
4. Experimental
4.1. General
All non-aqueous reactions were carried out under oxygen-free
Ar atmosphere using flame-dried glassware. Et2O and THF were
freshly distilled from sodium and benzophenone. 2-MeTHF, TMEDA
and Me3SiCl were purified by short-path distillation over CaH2
before use. Benzaldehyde was purified by Kügelrohr distillation.
DMF was used directly from the Pure Solv. MD-7 purification sys-
tem. s-BuLi was titrated against N-benzylbenzamide before use
[23]. Flash column chromatography was carried out according to
standard techniques using silica gel (60 Å, 220e440 mesh particle
Entry
n1/mL minꢀ1
0.50
1.00
1.25
1.67
n 2/mL minꢀ1
0.10
0.20
0.25
0.33
Time (sec)
10
5
4
3
Yield of 3 (%)a
1
2
3
4
34
53
59
59
a
Yield after purification by chromatography.
Boc pyrrolidine at 0 ꢁC (see Table 2), performing such lithiation
reactions on scale will be practically challenging due to the need for
fast addition of the s-BuLi and issues with mixing and heat dissi-
pation. We therefore turned our attention to the development of a
continuous flow process [17e21] for the synthesis of silyl pyrroli-
dine 3 at 0 ꢁC. As shown in Scheme 1, using s-BuLi/THF or s-BuLi/
TMEDA in THF at 0 ꢁC for 5 s gave the best batch yields of silyl
pyrrolidine 3 (59% and 66% respectively). Thus, suspecting that
using THF as the solvent and employing TMEDA helps to stabilise
the lithiated N-Boc pyrrolidine, we employed these conditions and
investigated the effect of reaction time on the isolated yield of silyl
pyrrolidine 3 (Table 3).
Using a Uniqsis FlowSyn system (see ESI for set-up) fitted with a
T-mixer, a pre-cooled stream of N-Boc pyrrolidine 1 and TMEDA
were mixed with s-BuLi at 0 ꢁC, before flowing through a 0.1 mL
microtube reactor. Subsequent trapping with Me3SiCl in THF solu-
tion in a flask at 0 ꢁC resulted in formation of silyl pyrrolidine 3
(Table 3). With a residence time of 10 s, silyl pyrrolidine 3 was
isolated in a disappointing 34% yield after chromatography (entry
1). Reducing the residence time to 5 s led to a significantly
improved yield of 53% of silyl pyrrolidine 3 (entry 2). Further
reduction in residence time to 4 s or 3 s gave silyl pyrrolidine 3 in
59% yield (entries 3 and 4). These last two results are comparable
with the diamine-free batch synthesis of silyl pyrrolidine 3 for 5 s at
0 ꢁC (see Table 1, entry 8). However, of significance, the continuous
flow process will be amenable to scale-up. The results presented in
Table 3 represent the first example of a lithiation-trapping reaction
of a N-Boc heterocycle using flow chemistry.
size 40e63
mm) purchased from Sigma-Aldrich or Fluka silica gel,
35e70 m, 60 Å and the solvent system as stated. Thin layer
m
chromatography was carried out using Merck TLC Silica gel 60G
F254 aluminium backed plates (100390 Supelco). Proton
(400 MHz) and carbon (100.6 MHz) NMR spectra were recorded on
a Jeol ECX-400 instrument using an internal deuterium lock. For
samples recorded in CDCl3, chemical shifts are quoted in parts per
million relative to CHCl3 (dH 7.26) and CDCl3 (dC 77.0, central line of
triplet). Carbon NMR spectra were recorded with broad band pro-
ton decoupling and assigned using DEPT experiments. Coupling
constants (J) are quoted in hertz. Infrared spectra were recorded on
a PerkinElmer UATR 2 FT-IR spectrometer. Electrospray high and
low resonance mass spectra were recorded at room temperature on
a Bruker Daltronics microOTOF spectrometer. N-Boc pyrrolidine 1
was prepared according to the literature procedure [24].
4.2. General procedure A: lithiation-trapping in THF or 2-MeTHF
s-BuLi (1.3 M solution in hexanes,1.3 eq.) was added dropwise to
a stirred solution of N-Boc pyrrolidine 1 (1.0 eq.) in THF or 2-MeTHF
(7 mL) at the specified temperature (ꢀ30 ꢁCe20 ꢁC) under Ar. The
resulting solution was stirred at the specified temperature for the
specific time (2 se5 min). Then, the electrophile (Me3SiCl, PhCHO
or DMF) (2.0 eq.) was added. The resulting solution was stirred at
the specified temperature for 10 min and then allowed to warm to
rt over 1 h. Saturated NH4Cl(aq) (10 mL) was added and the two
layers were separated. The aqueous layer was extracted with Et2O
(3 ꢄ 10 mL) and the combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give the crude product.
Table 1.
3. Conclusion
In conclusion, an exploration of temperatures of ꢀ30 ꢁC and
above for the rapid “high” temperature lithiation-trapping of N-Boc
pyrrolidine 1 has led to the identification of two new sets of reac-
tion conditions. Diamine-free lithiation in 2-MeTHF works well at
4.3. General procedure B: lithiation-trapping in 2-MeTHF or Et2O
with TMEDA
either ꢀ20 ꢁC (2 min) or 0 ꢁC (just 5 s) delivering
a-substituted
s-BuLi (1.3 M solution in hexanes,1.3 eq.) was added dropwise to
a stirred solution of N-Boc pyrrolidine 1 (1.0 eq.) and TMEDA (1.3
eq.) in 2-MeTHF or Et2O (7 mL) at the specified temperature
(ꢀ30 ꢁCe20 ꢁC) under Ar. The resulting solution was stirred at the
specified temperature for the specific time (2 se5 min). Then, the
electrophile (Me3SiCl, PhCHO or DMF) (2.0 eq.) was added. The
resulting solution was stirred at the specified temperature for
10 min and then allowed to warm to rt over 1 h. Saturated NH4Cl(aq)
(10 mL) was added and the two layers were separated. The aqueous
layer was extracted with Et2O (3 ꢄ 10 mL) and the combined
organic layers were dried (MgSO4) and evaporated under reduced
pressure to give the crude product. Table 1.
pyrrolidines 2, 3 or 4 in 50e69% yields. From a green chemistry
perspective, these conditions represent significant improvements
on those previously used as the temperatures are higher (and so
there would be less energy required to cool larger-scale reactions)
and the petroleum-derived solvents Et2O and THF have been
replaced by the biomass-derived, sustainable solvent, 2-MeTHF.
From a mechanistic perspective, we have also shown that lower
yields at higher temperatures and/or longer lithiation times are due
to the chemical instability of lithiated N-Boc pyrrolidine. Most
importantly, however, we have demonstrated that lithiation-
trapping of N-Boc heterocycles is possible at 0 ꢁC (in THF using s-
4

A. Kwong, J.D. Firth, T.J. Farmer et al.
Tetrahedron 81 (2021) 131899
4.4. General procedure C: lithiation-trapping in THF or 2-MeTHF
followed by incubation
4.7. 2-Trimethylsilyl pyrrolidine-1-carboxylic acid tert-butyl ester 3
Using general procedure A, s-BuLi (2.0 mL of a 2.6 M solution in
s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol) was
added dropwise to a stirred solution of N-Boc pyrrolidine 1 (171 mg,
hexanes, 2.6 mmol) and N-Boc pyrrolidine 1 (342 mg, 350 mL,
2.0 mmol) in 2-MeTHF (10 mL) at ꢀ20 ꢁC for 2 min and Me3SiCl
175
m
L,1.0 mmol) in THF or 2-MeTHF (7 mL) at ꢀ30 ꢁC under Ar. The
(326 mg, 381 mL, 3.0 mmol) gave the crude product. Purification by
resulting solution was stirred at ꢀ30 ꢁC for 5 min. The reaction flask
flash column chromatography on silica with 8:2 petrol-Et2O as
eluent gave silyl pyrrolidine 3 (254 mg, 52%) as a colourless oil, RF
was transferred to a 0 ꢁC bath and stirred at 0 ꢁC for 5 or 30 min.
Then, Me3SiCl (218 mg, 256
mL, 2.0 mmol) was added. The resulting
(8:2 petrol-Et2O) 0.4; 1H NMR (400 MHz, CDCl3)
d 3.56-3.41 (m, 1H,
solution was stirred at 0 ꢁC for 10 min and then allowed to warm to
rt over 1 h. Saturated NH4Cl(aq) (10 mL) was added and the two
layers were separated. The aqueous layer was extracted with Et2O
(3 ꢄ 10 mL) and the combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give the crude product.
Table 2.
NCH), 3.29-3.23 (m, 1H, NCH), 3.19-3.12 (m, 1H, NCH), 2.06-1.95 (m,
1H, CH), 1.82-1.72 (m, 3H, CH), 1.45 (s, 9H, CMe3), 0.04 (s, 9H,
SiMe3); 13C NMR (100.6 MHz, CDCl3) (rotamers)
d 154.6 (C]O), 79.2
(CMe3), 78.3 (CMe3), 47.6 (NCH), 47.0 (NCH2), 46.6 (NCH2), 28.5
(CMe3), 27.9 (CH2), 26.0 (CH2) 24.9 (CH2), ꢀ2.2 (SiMe3). Spectro-
scopic data consistent with those reported in the literature [26].
Table 1, entry 3(b) and Scheme 1.
4.5. General procedure D: lithiation-trapping in 2-MeTHF or Et2O
with TMEDA followed by incubation
4.8. N-(tert-Butoxycarbonyl)pyrrolidine-2-carboxaldehyde 4
Using general procedure A, s-BuLi (1.0 mL of a 1.3 M solution in
s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol) was
added dropwise to a stirred solution of N-Boc pyrrolidine 1 (171 mg,
hexanes, 1.3 mmol) and N-Boc pyrrolidine 1 (171 mg, 175
mL,
1.0 mmol) in 2-MeTHF (7 mL) at ꢀ20 ꢁC for 2 min and DMF (146 mg,
175 mL, 1.0 mmol) and TMEDA (151 mg, 195 mL, 1.3 mmol) in Et2O or
155
mL, 2.0 mmol) gave the crude product. Purification by flash
2-MeTHF (7 mL) at ꢀ30 ꢁC under Ar. The resulting solution was
stirred at ꢀ30 ꢁC for 5 min. The reaction flask was transferred to a
0 ꢁC bath and stirred at 0 ꢁC for 5 or 30 min. Then, Me3SiCl (218 mg,
column chromatography on silica with 1:1 hexane-Et2O as eluent
gave aldehyde 4 (105 mg, 52%) as a colourless oil, RF (1:1 hexane-
Et2O) 0.3; 1H NMR (400 MHz, CDCl3) (60:40 mixture of rotamers)
256 mL, 2.0 mmol) was added. The resulting solution was stirred at
d
9.56 (d, J ¼ 2.0 Hz, 0.4H, CHO), 9.46 (d, J ¼ 3.0 Hz, 0.6H, CHO), 4.24-
0 ꢁC for 10 min and then allowed to warm to rt over 1 h. Saturated
NH4Cl(aq) (10 mL) was added and the two layers were separated.
The aqueous layer was extracted with Et2O (3 ꢄ 10 mL) and the
combined organic layers were dried (MgSO4) and evaporated under
reduced pressure to give the crude product. Table 2.
4.17 (m, 0.4H, NCH), 4.05 (ddd, J ¼ 8.5, 6.0, 3.0 Hz, 0.6H, NCH), 3.61-
3.38 (m, 2H, NCH), 2.20-1.74 (m, 4H, CH), 1.48 (s, 4H, CMe3), 1.43 (s,
5H, CMe3); 13C NMR (100.6 MHz, CDCl3) (rotamers)
d 200.7 (C]O,
CHO), 200.5 (C]O, CHO), 154.0 (C]O, Boc), 80.6 (CMe3), 80.2
(CMe3), 65.0 (NCH), 64.8 (NCH), 46.8 (NCH2), 46.7 (NCH2), 28.4
(CMe3), 28.2 (CMe3), 28.0 (CH2), 26.7 (CH2) 24.6 (CH2), 23.9 (CH2).
Spectroscopic data consistent with those reported in the literature
[27]. Scheme 1.
4.6. 2-(Hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid tert-
butyl ester syn-2 and anti-2
Using general procedure A, s-BuLi (1.0 mL of a 1.3 M solution in
4.9. General procedure E: continuous flow synthesis of 2-
hexanes, 1.3 mmol) and N-Boc pyrrolidine 1 (171 mg, 175
m
L,
trimethylsilyl pyrrolidine-1-carboxylic acid tert-butyl ester 2
1.0 mmol) in 2-MeTHF (7 mL) at ꢀ20 ꢁC for 2 min and benzaldehyde
(228 mg, 203
m
L, 2.0 mmol) gave the crude product. Purification by
A Uniqsis FlowSyn system fitted with a T-mixer and a 0.1 mL
reaction tube (0.5 mm ID ꢄ 50 cm PTFE tubing) was flushed with
anhydrous THF (100 mL) under N2 and the pre-mixer tubing, mixer
and reaction tubing was cooled to 0 ꢁC. The end of the reaction
flash column chromatography on silica with 98:2 CH2Cl2-acetone as
eluent gave pyrrolidine syn-2 (119 mg, 43%) as a colourless oil, RF
(98:2 CH2Cl2-acetone) 0.4; 1H NMR (400 MHz, CDCl3)
d 7.38-7.27
(m, 5H, Ph), 5.93 (br s, 1 H, OH), 4.53 (br d, J ¼ 7.5 Hz 1H, OCH), 4.09
(td, J ¼ 7.5, 5.0 Hz, 1H, NCH), 3.50-3.42 (m, 1H, NCH), 3.39-3.28 (m,
1H, NCH), 1.78-1.65 (m, 2H, CH), 1.65-1.56 (m, 2H, CH), 1.52 (s, 9H,
tubing was added to a 2-neck RBF containing Me3SiCl (761
6.0 mmol, 2.0 eq.) at 0 ꢁC under N2. A solution of N-Boc pyrrolidine
1 (526 L, 3.0 mmol, 1.0 eq., 0.20 M) and TMEDA (585 L, 3.9 mmol,
mL,
m
m
CMe3); 13C NMR (100.6 MHz, CDCl3)
d
158.5 (C]O), 141.3 (ipso-Ph),
1.3 eq., 0.26 M) in anhydrous THF (15 mL) under N2 was pumped
through the FlowSyn system at a flow rate between 0.5 and
1.67 mL minꢀ1. Simultaneously, s-BuLi (1.3 M solution in hexanes,
3.0 mL, 3.9 mmol,1.3 eq.) was pumped through the FlowSyn system
at a flow rate between 0.10 and 0.33 mL minꢀ1 from a 3 mL injection
loop placed after the peristaltic pump. After 9e30 min, the flow
reactor was stopped and the reaction was quenched with saturated
NH4Cl(aq) (10 mL). Et2O (20 mL) was added and the two layers were
separated. The aqueous layer was extracted with Et2O (2 ꢄ 20 mL)
and the combined organic extracts were dried (MgSO4) and evap-
orated under reduced pressure to give the crude product.
128.8 (Ph), 128.6 (Ph), 127.2 (Ph), 81.1 (OCH), 79.5 (CMe3), 65.5
(NCH), 47.9 (NCH2), 28.8 (CH2), 28.7 (CMe3), 24.0 (CH2), a 65:35
mixture (by 1H NMR spectroscopy) of pyrrolidine anti-2 and syn-2
(4 mg, 1%) as a colourless oil and pyrrolidine anti-2 (70 mg, 25%) as
a colourless oil, RF (98:2 CH2Cl2-acetone) 0.3; 1H NMR (400 MHz,
CDCl3) (75:25 mixture of rotamers) d 7.41-7.22 (m, 5H, Ph), 5.49 (br
s, 0.75H, OH), 5.17 (br s, 0.25H, OH), 4.86 (br s, 0.75H, OCH), 4.32 (br
s, 0.75H, NCH), 3.97 (br s, 0.25H, OCH), 3.57 (br s, 0.25H, NCH), 3.30
(br s, 1H, NCH), 2.81 (br s, 0.75H, NCH), 2.30 (br s, 0.25H, NCH),
2.04-1.87 (m, 1H, CH), 1.86-1.66 (m, 1H, CH), 1.57 (br s, 3.5 H, CMe3),
1.52 (br s, 5.5 H, CMe3), 1.20-1.09 (m, 1H, CH), 0.93-0.79 (m, 1H, CH);
13C NMR (100.6 MHz, CDCl3)
d
159.8 (C]O), 157.4 (C]O), 141.9
4.10. 2-Trimethylsilyl pyrrolidine-1-carboxylic acid tert-butyl ester
3
(ipso-Ph), 141.3 (ipso-Ph), 128.5 (Ph), 128.3 (Ph), 128.1 (Ph), 127.4
(Ph), 127.1 (Ph), 126.1 (Ph), 80.5 (CMe3), 80.4 (CMe3), 76.3 (COH),
63.3 (NCH), 47.9 (NCH2), 47.7 (NCH2), 28.6 (CMe3), 27.5 (CH2), 26.1
(CH2), 23.6 (CH2), 22.6 (CH2). Spectroscopic data consistent with
those reported in the literature [25]. The total yield of syn-2 and
anti-2 is 69%. Scheme 1.
Using general procedure E, N-Boc pyrrolidine 1 (526
3.0 mmol, 1.0 eq., 0.20 M) and TMEDA (585 L, 3.9 mmol, 1.3 eq.,
0.26 M) at 1.25 mL minꢀ1, s-BuLi (1.3 M solution in hexanes, 3.0 mL,
3.9 mmol, 1.3 eq.) at 0.25 mL minꢀ1 and Me3SiCl (761
L, 6.0 mmol,
mL,
m
m
5

A. Kwong, J.D. Firth, T.J. Farmer et al.
Tetrahedron 81 (2021) 131899
8071e8077;
2.0 eq.) for a total time of 12 min gave the crude product. Purifi-
cation by flash column chromatography on silica with 85:15 hex-
ane-Et2O as eluent gave silyl pyrrolidine 3 (433 mg, 59%) as a
colourless oil. Table 3, entry 3.
(f) M. Lüthy, M.C. Wheldon, C. Haji-Cheteh, M. Atobe, P.S. Bond, P. O’Brien,
R.E. Hubbard, I.J.S. Fairlamb, Bioorg. Med. Chem. 23 (2015) 2680e2694;
(g) D. Stead, P. O’Brien, A. Sanderson, Synlett 26 (2015) 2381e2384;
(h) D.J. Firth, P. O’Brien, L. Ferris, J.D. Firth, P. O’Brien, L. Ferris, J. Am. Chem.
Soc. 138 (2016) 651e659;
(i) J.D. Firth, P. O’Brien, L. Ferris, J. Org. Chem. 82 (2017) 7023e7031;
(j) J.D. Firth, G. Gelardi, P.J. Rayner, D. Stead, P. O’Brien, Heterocycles 97 (2018)
1288e1303;
Declaration of competing interest
(k) T.D. Downes, S.P. Jones, H.F. Klein, M.C. Wheldon, M. Atobe, P.S. Bond,
J.D. Firth, N.S. Chan, L. Waddelove, R.E. Hubbard, D.C. Blakemore, C. De Fusco,
S.D. Roughley, L.R. Vidler, M.A. Whatton, A.J.A. Woolford, G.L. Wrigley,
P. O’Brien, Chem. Eur J. 26 (2020) 8969e8975.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[12] G. Barker, P. O’Brien, K.R. Campos, Org. Lett. 12 (2010) 4176e4179.
[13] For asymmetric lithiation-trapping of N-Boc heterocycles at temperatures as
high as e20 ꢁC, see:, G. Gelardi, G. Barker, P. O’Brien, D.C. Blakemore, Org. Lett.
15 (2013) 5424e5427.
Acknowledgments
[14] R.B. Bates, L.M. Kroposki, D.E. Potter, J. Org. Chem. 37 (1972) 560e562.
[15] (a) D.F. Aycock, Org. Process Res. Dev. 11 (2007) 156e159;
(b) V. Antonucci, J. Coleman, J.B. Ferry, N. Johnson, M. Mathe, J.P. Scott, J. Xu,
Org. Process Res. Dev. 15 (2011) 939e941.
We thank the University of York and the Wild Fund for funding
(AK).
[16] For a review on the use of 2-MeTHF as a solvent for organometallic reactions,
see:, S. Monticelli, L. Castoldi, I. Murgia, R. Senatore, E. Mazzeo, J. Wackerlig,
E. Urban, T. Langer, V. Pace, Monatsch Chem 148 (2017) 37e48.
[17] A. Nagaki, Tetrahedron Lett. 60 (2019) 150923.
[18] T. Zhao, L. Micouin, R. Piccardi, Helv. Chim. Acta 102 (2019), e1900172.
[19] M. Colella, A. Nagaki, R. Luisi, Chem. Eur J. 26 (2020) 19e32.
[20] M. Power, E. Alcock, G.P. McGlacken, Org. Process Res. Dev. 24 (2020)
1814e1838.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131899.
References
[21] For Recent Examples, See:. (a) S. Seghers, T.S.A. Heugebaert, M. Moens,
J. Sonck, J.W. Thybaut, C.V. Stevens, ChemSusChem 11 (2018) 2248e2254;
(b) A. Mambrini, D. Gori, C. Kouklovsky, H. Kim, J. Yoshida, V. Alezra, Eur. J. Org
Chem. 2018 (2018) 6754e6757;
[1] R.D. Taylor, M. MacCoss, A.D.G. Lawson, J. Med. Chem. 57 (2014) 5845e5859.
[2] E. Vitaku, D.T. Smith, J.T. Njardarson, J. Med. Chem. 57 (2014) 10257e10274.
[3] R.C. Doebele, L.E. Davis, A. Vaishnavi, A.T. Le, A. Estrada-Bernal, S. Keysar,
A. Jimeno, M. Varella-Garcia, D.L. Aisner, Y. Li, P.J. Stephens, D. Morosini,
B.B. Tuch, M. Fernandes, N. Nanda, J.A. Low, Canc. Discov. 5 (2015) 1049e1057.
[4] J. Wu, M. Zhang, D. Liu, J. Hematol. Oncol. 9 (2016) 21.
[5] G.J. Tanoury, M. Chen, Y. Dong, R. Forslund, V. Jurkauskas, A.D. Jones,
D. Belmont, Org. Process Res. Dev. 18 (2014) 1234e1244.
(c) T. von Keutz, F.J. Strauss, D. Cantillo, C.O. Kappe, Tetrahedron 74 (2018)
3113e3117;
(d) M.A. Ganiek, M.V. Ivanova, B. Martin, P. Knochel, Angew. Chem. Int. Ed. 57
(2018) 17249e17253;
€
(e) M. Kockinger, T. Ciaglia, M. Bersier, P. Hanselmann, B. Gutmann,
[6] P. Beak, W.-K. Lee, Tetrahedron Lett. 30 (1989) 1197e1200.
[7] K. Kasten, N. Seling, P. O’Brien, in: Enantioselective LithiationeSubstitution of
NitrogeneContaining Heterocycles, vol. 100, John Wiley & Sons, Inc., 2019,
pp. 255e328.
[8] A. Klapars, K.R. Campos, J.H. Waldman, D. Zewge, P.G. Dormer, C. Chen, J. Org.
Chem. 73 (2008) 4986e4993.
[9] (a) D. Xiao, B.J. Lavey, A. Palani, C. Wang, R.G. Aslanian, J.A. Kozlowski, N.-
Y. Shih, A.T. McPhail, G.P. Randolph, J.E. Lachowicz, R.A. Duffy, Tetrahedron
Lett. 46 (2005) 7653e7656;
(b) B. Le Bourdonnec, A.J. Goodman, T.M. Graczyk, S. Belanger, P.R. Seida,
R.N. DeHaven, R.E. Dolle, J. Med. Chem. 49 (2006) 7290e7306.
[10] L.S. Bennie, W.J. Kerr, M. Middleditch, A.J.B. Watson, Chem. Commun. 47
(2011) 2264e2266.
C.O. Kappe, Green Chem. 20 (2018) 108e112;
(f) C. Stueckler, P. Hermsen, B. Ritzen, M. Vasiloiu, P. Poechlauer, S. Steinhofer,
A. Pelz, C. Zinganell, U. Felfer, S. Boyer, M. Goldbach, A. de Vries, T. Pabst,
G. Winkler, V. LaVopa, S. Hecker, C. Schuster, Org. Process Res. Dev. 23 (2019)
1069e1077;
(g) J.Y.F. Wong, J.M. Tobin, F. Vilela, G. Barker, Chem. Eur J. 25 (2019)
12439e12445;
(h) A.L. Dunn, D.C. Leitch, M. Journet, M. Martin, E.A. Tabet, N.R. Curtis,
G. Williams, C. Goss, T. Shaw, B. O’Hare, C. Wade, M.A. Toczko, P. Liu, Or-
ganometallics 38 (2019) 129e137;
(i) P. Sagmeister, J.D. Williams, C.A. Hone, C.O. Kappe, React. Chem. Eng. 4
(2019) 1571e1578;
ꢀ
(j) G. Vile, G. Schmidt, S. Richard-Bildstein, S. Abele, J. Flow Chem. 9 (2019)
[11] (a) G. Carbone, P. O’Brien, G. Hilmersson, J. Am. Chem. Soc. 132 (2010)
15445e15450;
19e25.
[22] A. Maercker, Angew. Chem. Int. Ed. 26 (1987) 972e989.
[23] A.F. Burchat, J.M. Chong, N. Nielsen, J. Organomet. Chem. 542 (1997) 281e283.
[24] R.K. Dieter, S. Li, J. Org. Chem. 62 (1997) 7726e7735.
[25] J.L. Bilke, S.P. Moore, P. O’Brien, J. Gilday, Org. Lett. 11 (2009) 1935e1938.
[26] P. Beak, S.T. Kerrick, S. Wu, J. Chu, J. Am. Chem. Soc. 116 (1994) 3231e3239.
[27] P. Beak, W.K. Lee, J. Org. Chem. 58 (1993) 1109e1117.
(b) D. Stead, G. Carbone, P. O’Brien, K.R. Campos, I. Coldham, A. Sanderson,
J. Am. Chem. Soc. 132 (2010) 7260e7261;
(c) G. Barker, J.L. McGrath, A. Klapars, D. Stead, G. Zhou, K.R. Campos,
P. O’Brien, P. O’Brien, J. Org. Chem. 76 (2011) 5936e5953;
(d) N.S. Sheikh, D. Leonori, G. Barker, J.D. Firth, K.R. Campos, A.J.H.M. Meijer,
P. O’Brien, I. Coldham, J. Am. Chem. Soc. 134 (2012) 5300e5308;
(e) P.J. Rayner, P. O’Brien, R.A. Horan, J. J. Am. Chem. Soc. 135 (2013)
6