Synthesis of 2-substituted pyrrolidines from nitriles

Article abstract of DOI:10.1016/j.tetlet.2013.06.075

A novel and synthetically facile production of 2-substituted pyrrolidines from commercially available nitriles is reported herein. This methodology is operationally simple, and only requires the use of an extraction and a single chromatographic purificati

Full text of DOI:10.1016/j.tetlet.2013.06.075

Tetrahedron Letters 54 (2013) 5001–5003
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Tetrahedron Letters
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Synthesis of 2-substituted pyrrolidines from nitriles
⇑
P. Veeraraghavan Ramachandran , Wataru Mitsuhashi, Daniel R. Nicponski
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Dr. West Lafayette, IN 47907, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and synthetically facile production of 2-substituted pyrrolidines from commercially available
nitriles is reported herein. This methodology is operationally simple, and only requires the use of an
extraction and a single chromatographic purification to furnish the title compounds in high purity and
very good yields.
Received 6 May 2013
Revised 11 June 2013
Accepted 16 June 2013
Available online 27 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolidines
Nitriles
Hydroboration
Multi-step
Protecting group-free
Alkaloids are one of the most important classes of natural prod-
ucts, often exhibiting outstandingly potent biological activities.1
Pyrrolidine-containing compounds are an especially important
subclass of this group, as a variety of synthetic pharmaceuticals
and natural toxins have been reported which contain this struc-
tural motif. For example, cocaine,2 lepadiformine,3 ptilomycalin
A,4 and lapidilectine B5 are natural products with pyrrolidine deriv-
atives in their structures (Fig. 1). Furthermore, pyrrolidine deriva-
tives many times serve as the building blocks for ligands in
catalysis chemistry.6 We have been especially interested in
2-substituted pyrrolidines, as they have been shown to possess a
variety of physiological and pharmacological effects (e.g., nicotine,
proline derivatives, ONO-1603,7 and racetam drugs8).
A variety of methods have been reported in the literature detail-
ing the construction of this important functionality. In certain
cases, they can provide access to these compounds with a variety
of different functional groups at the 2-position, without requiring
an N-protection strategy. For example, Xu and co-workers have de-
scribed the preparation of pyrrolidines from amino alcohols, with-
out a protection-deprotection sequence, via the formation of the
amino chlorides, followed by cyclization.9 The asymmetric hydro-
genation of 2-substitued pyrrolines has been described,10 but this
strategy requires the preemptive synthesis of these same pyrro-
lines. In another report, 1,4-butanediol derivatives have been di-
rectly converted to pyrrolidine scaffoldings without protection
under the conditions of iridium(III) catalysis using elevated tem-
peratures.11 Similarly, Singaram and co-workers described the
benzylamination of the bismesylate derivatives of 1,4-diols as a
route to pyrrolidines.12
We recently reported a convenient synthesis of 2-substituted
and 2,3-disubstituted tetrahydrofurans in a one-pot procedure that
involved Brown’s allyl/crotylboration of aldehydes, followed by
iodination and cyclization.13 Additionally, we previously described
the production of homoallylic amines through an allyl/crotylbora-
tion strategy, using in situ-produced imines.14 We posited that the
application of a strategy similar to these two transformations
would allow direct access to these 2-substituted pyrrolidines di-
rectly from commercially available nitriles. Specifically, we envis-
aged using a one-pot procedure that would employ a sequence
involving: reduction, allylation, hydroboration, iodination, and
cyclization (Scheme 1, top pathway).
To determine the feasibility of this synthetic route, we chose to
study this sequence using benzonitrile as the model substrate. To
this end, an achiral allylation of the produced N-aluminoimine
with the simple Grignard reagent allylmagnesium bromide was
performed. Due to its difficult preparation, inherent instability,
and the fact that it did not offer improved conversions, the equiv-
alent reaction with allyldicyclohexylborane was found to be infe-
rior. Additionally, we successfully extended this one-pot
procedure to include the hydroboration of the formed homoallylic
amine using a variety of boranes, thereby providing 4-amino-4-
substitued-butan-1-ols, which were isolated by simple extraction
in high enough purity to carry forward without additional purifica-
tion. Unlike our previous report describing the synthesis of tetra-
hydrofurans,13 the iodine-promoted cyclization did not provide
the expected pyrrolidine product under any of the screened condi-
tions. As such, we sought to modify our approach, and discovered
that the use of thionyl chloride in a reverse addition9 provided,
⇑
Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.075

5002
P. V. Ramachandran et al. / Tetrahedron Letters 54 (2013) 5001–5003
Table 1
H
H
Application of six-step procedure to a variety of nitriles
H13C6
HO
R
N
H
N
i) DIBAL-H
N
H
N
NH2
O
ii) AllylMgBr
i) SOCl2
RCN
R
OH
R'
Racetam Drugs
iii) BH3 DMS
iv) 3M NaOH
H2O2
ii) 5M NaOH
R
Pyrrolidine
(-)-Lepadiformine
(crude)
Entry
R=
Pyrrolidine
Yielda
36
%
CO2Me
OBz
N
O
HN
N
1
2
1
O
N
MeO2C
N
2
3
17
25
MeO
Cocaine
(+)-Lapidilectine B
Nicotine
Figure 1. Pyrrolidine and several molecules containing its structural derivatives.
3
4
i) DIBAL-H
ii) AllylMgBr
iii) HBR2
F
NH2
iv) I2, NaOMe
PhCN
PhCN
BR2
Ph
4
17
H
N
F
S
Ph
5
6
5
6
17
22
i) DIBAL-H
ii) AllylMgBr
NH2
i) SOCl2
OH
iii) BH3 DMS
iv) [O]
ii) NaOH (aq)
Ph
7
8
7
8
4
4
Used Crude Material
Scheme 1. Initial (upper) and modified (lower) approaches to pyrrolidines from
nitriles.
a
Isolated overall yield of analytically pure product after column
chromatography.
upon subsequent aqueous workup, the desired pyrrolidine prod-
ucts. (Scheme 1, bottom pathway). We were gratified to discover
that the application of these conditions allowed for the formation
of these pyrrolidines from nitriles in six synthetic steps, but which
required only two purifications (one of them being extractive, the
other chromatographic).
to 81:19 occurred during the oxidation–cyclization protocol, as
determined by 1H NMR analysis of the N-menthylated product
[formed by the reaction of 2-phenylpyrrolidine with (À)-menthyl
chloroformate]. Further work in obtaining enantioenriched pyrrol-
idines through this sequence, along with the extension of this
methodology to the crotylation and alkoxyallylboration analogs,
is ongoing, and will be reported at a later date.
In conclusion, we have developed a straightforward, syntheti-
cally facile procedure for the production of 2-substituted pyrrol-
idines,16 which starts from commercially available nitriles, and
proceeds in very good yields. In contrast to other reported meth-
ods, this route does not require any tedious purifications, requiring
instead only a single performance of column chromatography.
With the optimized conditions for this six-step, high-yielding
transformation in hand, we applied this protocol to a series of ni-
triles of varying steric and electronic properties (Table 1). As can
be seen from the table, a variety of nitrile derivatives were toler-
ated under these conditions, including both electron-rich (entry
2) and electron-poor aromatic ones (entry 4), as well as heteroar-
omatic (entry 5) and polyaromatic nitriles (entry 3). In accord with
our previous observation that aliphatic nitrile reductions/allyla-
tions using similar processes furnish lower yields than do their aro-
matic counterparts,15 the use of heptanonitrile (entry 7) and
cyclohexancarbonitrile (entry 8) furnished lower overall yields. In
contrast, the use of benzyl cyanide provided the corresponding
pyrrolidine in excellent yield (entry 6). Overall, this six-step proce-
dure provided very high isolated yields, averaging 75% for each
step, and 18% (average) overall.
Acknowledgment
We would like to sincerely thank the Herbert C. Brown Center
for Borane Research for financial support of this project.
Through the incorporation of our previously reported reduc-
tion–allylboration–hydroboration sequence parameters,15 the
application of this methodology to the asymmetric synthesis of
pyrrolidines was next attempted. (In this case, we have found that
the use of DIBAL-H is superior to that of lithium triethylborohy-
dride, and opted for the use of the former in the present study.)
In this manner, we obtained the expected 2-phenylpyrrolidine
product. The incorporation of Brown’s isopinocampheyl ligand
during the allylation step provided the expected stereoinduction,
but necessitated the use of an additional acid-base extraction of
the aminol derivative to rid said product of the formed iso-
pinocampheol byproduct. Unexpectedly, a degradation of the chi-
rality occurred, as a decrease in the enantiomeric ratio from 94:6
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.075.
References and notes
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To
equiv) in 2 mL Et2O was added 0.18 mL DIBAL-H (1.03 mmol, 1.05 equiv) at
0 °C, and the reaction mixture was stirred for 1 h. After this 1.47 mL
a round bottom flask containing 0.10 mL benzonitrile (0.98 mmol, 1.0
,
allylmagnesium bromide (1.0 M in Et2O, 1.47 mmol, 1.5 equiv) was then added
at À78 °C, and the mixture was stirred for 24 h, then slowly warmed to 25 °C.
After this , 0.15 mL BH3ÁDMS (ꢀ10 M, 1.47 mmol, 1.5 equiv) was then added to
the solution at 0 °C, followed by 2 mL THF (added to help solvate the reaction
mixture). After stirring for 24 h at 25 °C, 0.2 mL MeOH, 1 mL 3 M aqueous
NaOH, and 1 mL 30% H2O2 were slowly and sequentially added to the mixture
at 0 °C. The product was then extracted with Et2O (3 Â 15 mL), then solvent
was removed under reduced pressure. The crude mixture was then dissolved in
5 mL 1,2-DME, and was subsequently transferred into another round bottom
flask that had been charged with 0.14 mL SOCl2 (1.96 mmol, 2 equiv) at 0 °C.
The reaction mixture was stirred for 3 h at 25 °C, then 1 mL aqueous 5 M NaOH
was added at 0 °C. After stirring for an additional 4 h at 0 °C, the product was
extracted with Et2O (3 Â 15 mL), then the solvent was removed under reduced
pressure. The crude product was purified via column chromatography to
furnish 2-phenylpyrrolidine.
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16. Representative experimental:
H
N
i) Reduction
ii) Allylation
iii) Hydroboration
iv) Oxidation
NH2
Ph
i) Chlorination
ii) Cyclization
PhCN
OH
Ph