The diastereoselective synthesis of 2,3-diaryl-3-cyano-substituted pyrrolidines via the MgI2 mediated ring expansion of aryl cyclopropyl nitriles

Article abstract of DOI:10.1016/j.tetlet.2020.152325

The MgI₂ mediated reaction of aryl substituted cyclopropyl nitriles with tosyl aldimines to give 2,3-diaryl-3-cyano-substituted pyrrolidines has been demonstrated. In all cases, the trans-diastereoisomer was determined to be the major product.

Full text of DOI:10.1016/j.tetlet.2020.152325

Tetrahedron Letters 61 (2020) 152325
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The diastereoselective synthesis of 2,3-diaryl-3-cyano-substituted
pyrrolidines via the MgI2 mediated ring expansion of aryl
cyclopropyl nitriles
Darren Stead
Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The MgI2 mediated reaction of aryl substituted cyclopropyl nitriles with tosyl aldimines to give 2,3-dia-
ryl-3-cyano-substituted pyrrolidines has been demonstrated. In all cases, the trans-diastereoisomer was
determined to be the major product. The overall yield and diastereoselectivity of the reaction showed
some sensitivity to the electronic and steric demands of the aryl cyclopropyl nitriles and the tosyl aldi-
mines. Substitution with electron withdrawing substituents on both reacting partners proved beneficial
in terms of the yield and diastereoselectivity.
Received 26 June 2020
Revised 28 July 2020
Accepted 2 August 2020
Available online 19 August 2020
Keywords:
Ó 2020 Elsevier Ltd. All rights reserved.
Pyrrolidine synthesis
Cyclopropyl nitriles
MgI2
Ring expansion
Diastereoselective
The pyrrolidine motif is ubiquitous in Nature, making up the
core of over 80 complex alkaloids [1]. Many of these alkaloids have
profound biological effects, such as the addictive component of
tobacco, (ꢀ)-nicotine 1, the structurally more elaborate stimulant
cocaine 2 [2], as well as the venom of the Monomorium indicum
ant 3 (Fig. 1) [3]. Drug discovery programs have also sought to
exploit the pyrrolidine motif, using its basic nitrogen to improve
physiochemical properties or taking advantage of its 9 potential
points of substitution to achieve desirable vectors. Recent exam-
ples include cholinesterase inhibitors [4], selective SphK2 inhibi-
tors [5] and PROTACs targeting EGFR in an oncology setting [6].
As a consequence, research into the synthesis of pyrrolidines
has been extensive, with every bond within the ring being subject
to disconnection and a host of methodologies being used to intro-
duce functionality at each position, with cycloaddition and annula-
tion strategies proving popular [7]. Multicomponent, or multistep,
reactions offer an attractive avenue for pyrrolidine ring synthesis
because of the potential to quickly assemble pyrrolidines with
complex substitution patterns [8]. At AstraZeneca, we became
interested in 2,3-diaryl-3-cyano-substituted pyrrolidines. Litera-
ture syntheses of such motifs was limited [9–19], especially with-
out further decoration [20]. However, we were intrigued by the
MgI2 mediated synthesis of 2-aryl-3-keto-substituted pyrrolidines
via the multicomponent reaction of a cyclopropyl ketone and an
Fig. 1. Selected examples of natural products containing the pyrrolidine motif.
in situ generated aldimine, reported by Olsson and co-workers
[21]. This work was itself inspired by Carreria’s research into the
synthesis of spiro[pyrrolidine-3-30-oxindole] natural products
[22]. Building from these contributions, we hypothesized that an
electron withdrawing nitrile group could be used to activate an
aryl-cyclopropyl ring [23], towards ring opening by MgI2. Subse-
quent addition to an aldimine would lead to a 2,3-diaryl-3-
cyano-substituted pyrrolidine (Scheme 1). This would provide a
complementary approach to the elegant 1,3-dipolar cycloaddition
methodology recently described by Lan and Zhang to access similar
molecules [19].
From a drug discovery perspective, this approach would be par-
ticularly attractive because a number of 1-aryl-1-cyano substituted
cyclopropanes were commercially available, allowing rapid explo-
ration of SAR. Thus, we began our exploration with the commer-
cially available cyclopropane 4, the bromide of which could also
E-mail address: darren.stead@astrazeneca.com
https://doi.org/10.1016/j.tetlet.2020.152325
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
D. Stead / Tetrahedron Letters 61 (2020) 152325
mation in hand, we set about preparing several other aryl-cyclo-
propanes, using the conditions illustrated for benzonitrile 10a
(Scheme 4) and subjecting them to the pyrrolidine forming condi-
tions (Scheme 5 and Table 1).
Table 1 shows that in all cases the trans-diastereoisomer was
the major product of the reaction. It is clear that both electronic
and steric factors are affecting the yield and diastereoselectivity.
Although the overall isolated yield between entries 1 and 2 are
similar, the addition of the electron withdrawing nitrile in the
para-position (10a, entry 2) resulted in an improved diastereose-
lectivity, favoring the trans-diastereoisomer 11a.
Scheme 1. Proposed reaction for this work. Pg = protecting group.
Introduction of an ortho-fluorine (10c, entry 4) resulted in an
increase in the proportion of the cis-diastereoisomer 12c. This
effect was also observed with the ortho-chlorine and ortho-bro-
mine examples (entries 7 and 8), albeit with greater reduction in
overall yield, indicating that ortho-substitution is deleterious to
the reaction (vide infra). In contrast, meta-substitution does not
hinder the reaction (entry 5) and the reaction appears to tolerate
electron rich aromatics (entry 6, the yield before diastereoisomer
separation was 59% as 1.5:1 mix of trans to cis diastereoisomers),
although with reduced diastereoselectivity. These results indicate
that meta and para substitution is preferred for conversion to the
pyrrolidine ring and that electron poor aromatics give the highest
yields and trans-diastereoselectivities.
Scheme 2. Initial exploration: Reagents and conditions: Benzylamine (1 equiv.), 4-
fluorobenzaldehyde (1 equiv.), MgI2 (1.5 equiv.), THF, reflux, 16 h. Only minor signs
of conversion to the desired products observed by UPLC (approx. 5% conversion to
each diastereoisomer).
Intrigued by the observation that substitution on the cyclo-
propane with electron deficient aromatics gave the highest yields
and trans-diastereoselectivities, we next explored reacting ben-
zonitrile 10a with aldimines of varying steric and electronic
demands, to determine the scope of this reaction (Scheme 6 and
Table 2) [25].
provide a handle for further elaboration. Subjecting cyclopropane 4
to similar conditions to those described by Olsson and co-workers
[21], generating an imine in situ between benzylamine and
4-fluorobenzaldehyde, showed only minor signs of the desired
products, trans and cis pyrrolidines 5 and 6, by UPLC after 16 h at
reflux (Scheme 2).
Gratifyingly, we found that a range of aldimines successfully
underwent this reaction. The combination of the electron deficient
cyclopropane 10a and para-electron withdrawing groups on aldi-
mine 13 gave excellent overall yields and good diastereoselectivi-
ties (Table 2, entries 1 and 2). The trans-diastereoisomers were
produced in > 5:1 ratio over the cis-diastereoisomers, in each case.
Introduction of an electron donating para-methoxy group (entry 3)
saw a reduction in the diastereoselectivity, but a para-bromo sub-
stituent still resulted in good diastereoselectivity, with the trans-
diastereoisomer being isolated in > 70% yield (entry 4). Interest-
ingly, methyl substituted 13e, resulted in a significantly lower
trans-diastereoselectivity (3.84:1, entry 5), although these isomers
could not be separated by FCC or prep-HPLC. meta-Substitution
was tolerated with generally good yields and trans-diastereoselec-
tivities (entries 6–9), again with more electron deficient examples,
such as entry 8, giving the highest trans-diastereoselectivities.
ortho-Substituents gave slightly reduced overall yield (entries 10
and 11), however, the ortho-chlorine present in 13j (entry 10)
had a large impact on the trans-diastereoselectivity, although the
trans-diastereoisomer 14j was still the predominant product in a
ratio of 1.7:1. This effect on diastereoselectivity was not as marked
for the ortho-methoxy substituent (entry 11), with the result being
similar to the presence of a para-or meta-methoxy group (entries 3
and 9).
Despite only low conversion, this result did demonstrate that
the nitrile could activate the cyclopropane ring to attack by MgI2
and lead to the pyrrolidine products. Considering this reaction to
proceed via an analogous mechanism to that proposed by Olsson
and co-workers, it was not clear if the addition of the MgI2 to the
cyclopropyl ring was limiting the conversion, or if the reaction of
the resulting anion with the formed aldimine was the issue. Prag-
matically, it was simplest to investigate the latter, and so the cor-
responding tosyl-aldimine was prepared, reasoning that aldimine 7
would be more activated towards nucleophilic attack.
When tosyl aldimine 7 was reacted with cyclopropane 4
(Scheme 3), good conversion was apparent and gratifyingly the
trans and cis diastereoisomers, 8 and 9 respectively, were readily
separated by flash column chromatography (FCC) to give the
trans-diastereoisomer 8 in 51% yield and the cis-diastereoisomer
in 23% yield. The approximately 2:1 ratio of diastereoisomers 8
and 9 corresponded well with the expected ratio, as judged by
the 1H NMR spectrum of the crude product. The relative stereo-
chemistry was determined by 2D NMR spectroscopy [24].
We attempted to optimize the diastereomeric ratio of products
further (see ESI), however, no significant improvements were dis-
covered, with THF being the best solvent and the reaction being
seemingly insensitive to the equivalents of MgI2. With this infor-
Scheme 4. Preparation of aryl-cyclopropanes: Reagents and conditions for example
benzonitrile 10a: 4-(cyanomethyl)benzonitrile (1 equiv.), 1-bromo-2-chloroethane
Scheme 3. Reaction of tosyl aldimine
7
with cyclopropane 4: Reagents and
(1.5 equiv.), 50% (w/w) NaOH
(6 equiv.), N-benzyl-N,N-diethylethanaminium
(aq)
conditions: 4 (1 equiv.), 7 (1 equiv.), MgI2 (1.5 equiv.), THF, reflux 16 h.
bromide (8 mol%), 0 °C-rt, 4 days, (61%).

D. Stead / Tetrahedron Letters 61 (2020) 152325
3
Table 2
Aldimine scope from Scheme 6.
a
a
Entry Tosyl aldimine 13
Trans- ( )-14 (% yield)
14a (83)
Cis- ( )-15 (% yield)
15a (16)
1
2
3
4
14b (79)
14c (48)
14d (72)
15b (14)
15c (14)
15d (15)
Scheme 5. Reaction of tosyl aldimine
Reagents and conditions: Aryl cyclopropane (1 equiv.), 7 (1 equiv.), MgI2 (1.5
equiv.), THF, reflux 16 h.
7 with aryl cyclopropanes in Table 1:
14e (75)b
14f (73)
14g (62)
14h (70)
–
Table 1
5
6
7
8
Aryl cyclopropane scope from Scheme 5.
Entry Aryl cyclopropane
1
Trans- ( )-11 (% yield) a Cis-( )-12 (% yield) a
15f (15)
15g (14)
15h (12)
8 (51)
9 (23)
2
11a (68)
12a (7)
3
4
11b (61)
11c (40)
12b (20)
12c (32)
9
14i (60)
14j (43)
15i (15)
15j (25)
10
5
6
7
11d (61)
11e (20)b
11f (15)
12d (20)
12e (13)b
12f (9)
11
14k (54)
15k (17)
a
Yields of separated diastereoisomers unless otherwise noted.
3.84:1 mixture of trans:cis-diastereosisomers as no separation of diastereoiso-
mers was achieved by FCC or prep-HPLC.
b
8
11g (22)
12g (12)
a
Yields of separated diastereoisomers.
Chiral SFC used to separate diastereoisomers. 59% yield after FCC as a 1.5:1 ratio
b
of trans to cis diastereoisomers.
Fig. 2. Proposed mechanism.
Scheme 6. Reaction of benzonitrile cyclopropane 10a with tosyl aldimines 13 in
Table 2: Reagents and conditions: Aryl cyclopropane 10a (1 equiv.), aldimine
(1 equiv.), MgI2 (1.5 equiv.), THF, reflux 16 h.
increasing the rate of pyrrolidine formation. When the pyrrolidine
is formed, the stereochemistry is then fixed.
In summary, the MgI2 mediated reaction between a variety of
aryl-substituted cyclopropyl nitriles and a number of aldimines to
give 2,3-diaryl-3-cyano-substituted pyrrolidines has been devel-
oped. It was found that electron deficient aromatics on both reacting
partners was beneficial for the overall yield and obtaining good
trans-diastereoselectivity of the resulting pyrrolidine products.
The reaction requires no special reaction conditions, using either
reactants that are commercially available, or synthesized in one step
each from such reagents. All but one set of diastereoisomeric prod-
ucts were readily separated by FCC and/or HPLC, often giving the
trans-diastereoisomer of the pyrrolidine product in very good yield.
Although no mechanistic studies have been conducted, a rea-
sonable mechanism can be proposed (Fig. 2), which shares charac-
teristics with that proposed by Olsson and co-workers for
cyclopropyl ketones [21]. However, rationalization of a transition
state that explains the diastereoselectivity is more challenging.
The results in Tables 1 and 2 indicate that there are both steric
and electronic components of the selectivity. Increasing the steric
bulk of the aromatics results in an increase in steric clashes, dis-
rupting the transition state leading to lower diastereoselectivity.
The subtlety of the electronics of the system on the diastereoselec-
tivity may be indicative of the stereo-determining step being
reversible. Electron withdrawing groups on the aromatic ring could
potentially stabilize the magnesium alkanide, allowing formation
of the thermodynamically more stable Mannich product, resulting
in higher diastereoselectivities. The erosion of this selectivity by
electron donating groups on the aldimine, may be a result of
increasing the reactivity of the resulting magnesium amide,
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.

4
D. Stead / Tetrahedron Letters 61 (2020) 152325
[17] J. Wang, Y. Liu, Z. Wei, J. Cao, D. Liang, Y. Lin, H. Duan, J. Org. Chem. 85 (6)
Acknowledgements
(2020) 4047–4057.
[18] X.-J. Zou, W.-L. Yang, J.-Y. Zhu, W.-P. Deng, Chin. J. Chem. 38 (5) (2020) 435–
438.
[19] Y. Xiong, Z. Du, H. Chen, Z. Yang, Q. Tan, C. Zhang, L. Zhu, Y. Lan, M. Zhang, J.
Am. Chem. Soc. 141 (2) (2019) 961–971.
The author would like to thank Erin Braybrooke, Paul Davey and
David Longmire of AstraZeneca for determination of HRMS.
[20] Q. Shi, M.C. Meehan, M. Galella, H. Park, P. Khandelwal, J. Hynes, T.G.M. Dhar,
D. Marcoux, Org. Lett. 20 (2) (2018) 337–340.
[21] F. Bertozzi, M. Gustafsson, R. Olsson, Org. Lett. 4 (18) (2002) 3147–3150.
[22] P.B. Alper, C. Meyers, A. Lerchner, D.R. Siegel, E.M. Carreira, Angew. Chem. Int.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152325.
[23] Vinylcyclcopropanes have been activated with geminal dicyano-
substitutuents, to undergo palladium catalysed [3+2] cycloadditions with
imines to afford pyrrolidine products. See (a) Dieskau, A. P.; Holzwarth, M. S.;
Plietker, B., J. Am. Chem. Soc. 2012, 134 (11), 5048-5051. (b) Pursley, D.;
Plietker, B., Synlett 2014, 25 (16), 2316-2318. (c) Ling, J.; Laugeois, M.;
Ratovelomanana-Vidal, V.; Vitale, M. R., Synlett 2018, 29 (17), 2288-2292.
[24] After verification of several examples it became clear that the chemical shifts
of the NTsCHAr proton in the 1H NMR spectrum were indicative of the relative
stereochemistry, with the trans-diastereoisomer observed at lower ppm
(typically at around 4.85 ppm) than the cis-diastereoisomer (typically at
around 5.10 ppm).
[25] Representative procedure for 14a and 15a: To a stirred solution of 4-(1-
cyanocyclopropyl)benzonitrile 13a (200 mg, 1.19 mmol) and N-(4-
cyanobenzylidene)-4-methylbenzenesulfonamide 10a (338 mg, 1.19 mmol)
in THF (4 mL) was added magnesium iodide (496 mg, 1.78 mmol). The
resulting mixture was heated to reflux and stirred for 16 hours. The mixture
was allowed to cool to room temperature and water (10 mL) and EtOAc (20
mL) were added. The layers were separated and the aqueous layer was
extracted with EtOAc (2 x 20 mL). The combined organics were dried (phase
separation cartridge) and concentrated under reduced pressure to give the
crude product. The crude product was purified by flash silica chromatography,
elution gradient 0 to 60% EtOAc in heptane and by preparative HPLC (Waters
CSH C18 OBD column, 5m silica, 30 mm diameter, 100 mm length), using
decreasingly polar mixtures of water (containing 1% NH3) and MeCN as
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eluents
to
give
rac-4,4’-((2R,3S)-3-cyano-1-tosylpyrrolidine-2,3-diyl)
dibenzonitrile 14a (0.447 g, 83%) and rac-4,4’-((2R,3R)-3-cyano-1-
tosylpyrrolidine-2,3-diyl)dibenzonitrile 14b (0.088 g, 16%) as white foamy
solids.
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