Selective Formation of Functionalized α-Quaternary Malononitriles toward 5,5-Disubstituted Pyrrolopyrimidinones

Article abstract of DOI:10.1021/acs.orglett.7b01930

A modular, selective approach to complex α-tertiary substituted malononitriles is reported. The method takes advantage of β-ester-substituted α,α-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation-π interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones.

Full text of DOI:10.1021/acs.orglett.7b01930

Letter
pubs.acs.org/OrgLett
Selective Formation of Functionalized α‑Quaternary Malononitriles
toward 5,5-Disubstituted Pyrrolopyrimidinones
Alan Whitehead,* Yong Zhang,* Jamie McCabe Dunn, Edward C. Sherer, Yu-hong Lam,§
,
†
,†
‡
§
†
†
†
‡
†
John Stelmach, Aaron Sun, Melisa Shiroda, Robert K. Orr, Sherman T. Waddell,
and Subharekha Raghavan†
†
Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
‡
§
Process Chemistry and Modeling and Informatics, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States
*
S Supporting Information
ABSTRACT: A modular, selective approach to complex α-
tertiary substituted malononitriles is reported. The method
takes advantage of β-ester-substituted α,α-dinitrile alkenes as
highly reactive, chemoselective electrophiles for 1,4-additions
with organometallic nucleophiles to produce functionally and
sterically dense all-carbon quaternary centers. In the presence
of a chiral ester auxiliary bearing an aromatic ring, the 1,4-
addition occurs with good to excellent selectivity due to favorable cation−π interactions. The highly functionalized malononitriles
represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted
pyrrolopyrimidinones.
yrrolopyrimidine and -pyrimidinone structural motifs
Complex malononitriles of type 1 represent a significant
synthetic challenge due to the requisite reactivity of functional
groups and steric congestion at the all-carbon quaternary
position.
P
represent a growing class of fused heterocycles of
1
considerable interest in drug development. Compared to
closely related indoline or indolinone structural counterparts,
substituted pyrrolopyrimidine and -pyrimidinones remain less
explored, and general synthetic methods for their preparation
To address this, we envisioned a modular synthetic strategy
1
2
to sequentially introduce R /R functionalization utilizing 1,4-
conjugate addition of carbon nucleophiles to highly activated
tetrasubstituted malononitrile alkene 5 (Scheme 1). This
2
and functionalization, while growing, remain limited. Our own
efforts to discover a novel class of soluble guanylate cyclase
(
sGC) stimulators led to the identification of a promising series
3
of 5,5-disubstituted pyrrolopyrimidinones. Leveraging liter-
ature precedence first demonstrated for guanidines, pyrrolo-
Scheme 1. Strategy To Complex Malononitrile Reagents
4
pyrimidinones of general structure 3 could be assembled in a
convergent manner starting from malononitrile 1 and amidine
2
subunits (Figure 1). In this approach, the amidine/guanidine
approach takes advantage of broadly accessible β-keto esters
4
and commercially available or readily prepared organometallic
reagents. Although α,α-dinitrile alkenes are well established
partners for 1,4-addition reactions, little has been reported for
this reaction with increasingly electron-deficient dinitrile
alkenes containing β-ester substitution. While previous
examples of reactivity of general structure 5 have largely
focused on their use in cycloaddition reactions, an initial
report (5, R = CF ) disclosed a limited substrate scope for 1,4-
Figure 1. Complex malononitriles in the synthesis of pyrrolopyr-
imidines.
5
1
3
6
addition with unactiviated nucleophiles. Based on our interest
group condenses with the functionalized malononitrile to form
an intermediate aminopyrimidine ring that subsequently reacts
with the pendant ester to produce the fused pyrrolidinone ring.
While this method enables a convergent approach toward a
promising class of 5-substituted pyrrolopyrimidinones, the
utility of this method ultimately relies on access to highly
functionalized malononitriles.
in this complex malononitrile subunit, we endeavored to
explore the reactivity of varied alkenes of type 5 with carbon
nucleophiles to generate highly functionalized, sterically dense
Received: June 24, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
malononitriles affixed to all-carbon quaternary centers. Herein,
we report our efforts to access this structural motif, including
regioselectivity evaluation, substrate scope, diastereoselective
addition mediated by an ester chiral auxiliary, and application
toward the synthesis of an enantioenriched 5,5-disubstituted
pyrrolopyrimidinone of biological interest.
nucleophiles proceeded with high selectivity at the β position
with 5a. In the case of Ph-MgBr (1g), the high selectivity for
the β regioisomer (>20:1) could be reversed via addition of
stoichiometric copper to preferentially afford the α-
regioisomer. The analogues 5b and 5c were similarly reactive
and demonstrated consistently high levels of regioselectivity
with a range of organometallic reagents including aryl (1j,l),
heteroaryl (1i,m) and even alkyl nucleophiles (1k). Impres-
sively, even given the additional steric bulk of the cPr
substituent of 5c, highly steric congested quaternary carbon
centers were readily accessed through this method. The
exceptional reactivity of these alkenes is further evident in 1k
10
Substrates 5a and 5b were assembled via Knoevanagel
7
condensation and isolated via distillation (Scheme 2). The
Scheme 2. Synthesis of Alkenes 5a−c
that can be formed with ZnEt at cryogenic temperatures.
2
Having established the utility and regioselectivity of the
method to access diverse prochiral and racemic malononitriles,
we turned our focus to the asymmetric synthesis of the 1,4-
adducts. Given the high reactivity of the alkenes with
organometallic reagents, we focused on a chiral auxiliary
approach to access diastereomerically enriched malononitriles.
Starting with commercially available chiral alcohols, alkenes
bearing the ester auxiliaries were readily prepared via acid-
catalyzed esterification of α-ketoacids followed by Knoevanagel
condensation with malononitrile to provide moderate to good
yields of 8a−d (Scheme 4).
stability of 5b proved challenging, and care was necessary
during isolation to avoid formation of dimerized substrate 6. In
comparison, the c-Pr analogue 5c could be readily isolated as a
crystalline, bench-stable solid that did not undergo dimeriza-
tion.
With the alkenes in hand, the substrate scope and
regioselectivity for the 1,4-addition reaction were explored
8
(Scheme 3). Starting with 5a, the alkene bearing β,β-diester and
Scheme 4. Synthesis of Alkenes Bearing Ester Auxiliary
Scheme 3. Regioselectivity and Substrate Scope of 1,4-
Addition Reaction with Carbon Nucleophiles
a
Initial attempts at diastereoselective addition with menthol
ester 8a proved disappointing in which a near 1:1 mixture of
diastereomers was observed for methyl and aryl Grignard
reagents (Table 1, entry 1 and 2). Phenyl-substituted menthol
analogue 8b failed to improve diastereoselectivity with methyl
Grignard (entry 3) and unexpectedly proved unreactive with
a
Table 1. Stereoselectivity with Chiral Ester Auxiliaries
aRegioselectivity was determined by crude 1H NMR. Standard
conditions utilized commercially available or in situ derived Grignards
b
at 0 to −30 °C in THF unless otherwise noted. Starting material 5a.
c
d
Starting material 5b. From treatment of 5c with Et Zn at −78 °C
2
e
f
warming to −40 °C. Starting material 5c. Treatment of 5c with in
situ derived organolithiate.
dinitrile substitution demonstrated a preference for addition at
the position β to the malononitrile. Some trends could be
a
1
9
Diastereomeric ratio (dr) was determined by crude H NMR or
chiral supercritical fluid chromatography (SFC). Standard conditions
utilize commercially available or in situ derived Grignards in THF; see
seen, with aliphatic Grignards providing lower levels of
regioselectivity, the most drastic example being c-pentyl-MgBr
that afforded 1e-α as the major isomer (examples 1a−c,e). The
one exception to this trend was c-PrMgBr, which gave high
b
c
the Supporting Information for details. MeMgCl, −78 °C. 2-
d
e
MeOPhMgBr, −78 °C. c-PrMgBr, −40 °C. 2-MeOPhMgBr, −40
f
g
°C. EthynylMgBr, 0 °C. Absolute stereochemistry of 8c was
confirmed by vibrational circular dichroism (VCD); see the SI.
2
selectivity for the desired isomer. In contrast, sp -type
B
DOI: 10.1021/acs.orglett.7b01930
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Organic Letters
Letter
larger nucleophiles (entry 4). Moving to ester auxiliary 8c, we
reasoned that closer proximity of the phenyl ring of the chiral
ester appendage to the site of 1,4-addition may improve facial
selectivity through improved conformational bias resulting from
potential π-stacking interactions with the alkene. Gratifyingly,
treatment of 8c with Me-MgCl provided a modest 6:1
diastereomeric ratio (dr) (9e). Furthermore, excellent diaster-
oselectivity was observed for larger alkyl nucleophiles leading to
substrates. Similarly, substitution of Me/t-Bu at the 3- and 3,5-
13
positions appeared to afford no improvement in selectivity. In
general, yields were high for the 1,4-addition reaction of methyl
Grignard with 11i affording both good diastereoselectivity
(12:1) and high yield (96%) in the formation of 12i.
11
Structural models for select transition states were studied by
DFT computations to investigate factors governing the
selectivity of the aryl-containing chiral auxiliaries. Exploring
1
4
9
f in >20:1 diastereoselectivity. When R = c-Pr (entries 7−9),
several conditions, proper selectivity ratios were only
obtained when dimeric Me-MgCl was included, as depicted
in Figure 2. Several density functionals were investigated, and it
diastereoselectivity was significantly reduced for methyl
Grignard addition (9g) but showed similarly high selectivities
for aryl (9h) and ethynyl (9i) nucleophiles.
Given the initial success with the trans-phenylcyclohexanol-
based ester 8c, we rationalized that substitution on the phenyl
ring of phenylcyclohexanol could further improve diasterose-
lectivities by affording a greater conformational bias. A focused
set of analogues to test this hypothesis were synthesized and
evaluated with our most challenging nucleophile, methyl
Grignard (Scheme 5). To enable rapid evaluation of varied
Scheme 5. trans-Phenylcyclohexanol Analogue Synthesis
auxiliaries, a simple high-throughput route to the custom chiral
alcohols was leveraged, starting with addition of an aryl
Grignard to cyclohexene oxide. The racemic trans-alcohols were
then readily separated via supercritical fluid chromatography
Figure 2. Transition-state structures calculated at the M06-2X/6-
3
1G** level with SMD implicit THF. Bond distances are for dashed
lines.
1
2
(
SFC), reacted with phenylglyoxylic acid, and condensed with
15
malononitrile to provide single enantiomer alkenes 11a−i.
With substituted aryl trans-cyclohexanoate auxiliaries in hand,
stereoselectivity for 1,4-conjugate addition with methyl
Grignard was explored (Scheme 6). Substrate scope included
was determined that quasiharmonic corrected free energies
calculated with M06-2X/6-31G** with SMD implicit THF
16
agreed best with experimental data.
Example 9a, containing a chiral auxiliary with an isopropyl
group trans to the ester substituent provided no diastereose-
lectivity following 1,4-addition consistent with calculations,
which showed the relative free energy difference in the two
transition states to be 0.0 kcal/mol. Alternatively, auxiliaries
which have an aryl group trans to the ester (such as 9e and 12i)
enable a favorable cation−π interaction between the second
Me-MgCl of the dimer and the auxiliary (Figure 2). The
estimated preference for the (R) configuration shifts from 0.0
to 3.3 or 3.8 kcal/mol. The energy differences overpredict the
observed selectivity potentially due to other active forms of the
nucleophile that were found to be nonselective in our model.
Scheme 6. Stereoselectivity for 1,4-Addition with 2-
a
Hydroxyphenyl-Substituted Auxiliary Analogues
17
With diastereomerically enriched 12i in hand, application
of the reagents toward the synthesis of 5,5-disubstituted
pyrrolopyrimidine sGC stimulator 14 was investigated (Scheme
7
). Coupling 12i with amidine 13 under mild conditions
afforded the desired substrate in high yield and with an
a
b
All diastereoselectivities were determined by chiral SFC. Isolated
yield.
Scheme 7. Enantioenriched Synthesis of an sGC Stimulator
electron-donating and electron-withdrawing substituents and
compounds with varying patterns of steric bulk at the 3−5
position of the aryl ring. A clear trend was observed with
increasing alkyl steric bulk at the 4-position as Me (11g) → i-Pr
(11h) → t-Bu (11i) provided incremental improvements in
selectivity affording up to a 12:1 selectivity with the tert-butyl
substituent. Interestingly, this same selectivity was not observed
with the 4-substituted Ph (11c), CF (11b), and O-i-Pr (11a)
3
C
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Letter
enantiomeric ratio (er) of 12:1 consistent with the selectivity of
Griebenow, N.; Knorr, A.; Wunder, F.; Li, V. M. J.; Kroh, W.;
Baerfacker, L. PCT Int Appl WO 2012004258, 2012.
(2) (a) See ref 1a. (b) Kobayashi, K.; Ono, R.; Yuba, S.; Hiyoshi, H.;
Umezu, K. Heterocycles 2015, 91, 1177. (c) Cheung, M.; Harris, P. A.;
Lackey, K. E. Tetrahedron Lett. 2001, 42, 999. (d) Sekhar, N. M.;
Acharyulu, P. V. R.; Anjaneyulu, Y. Tetrahedron Lett. 2011, 52, 4140.
1
2i. In the process of the transformation, the ester auxiliary 10i
18
is cleaved and can be recovered during purification. The
method enables access to substrates of type 14 without any
additional linear steps and represents a significant improvement
19
in overall yield of 14.
(e) Vaid, R. K.; Spitler, J. T.; Boini, S.; May, S. A.; Hoying, R. C.
In summary, regioselective 1,4-conjugate addition with
organometallic reagents to highly activated, tetrasubsituted
α,α-dinitrile alkenes affords a general, flexible approach to
highly functionalized, sterically congested malononitrile build-
ing blocks. Good to excellent stereoselectivity was achieved
with ester-based chiral auxiliaries, affording up to >20:1
diastereomeric ratios for a variety of nucleophiles. The high
selectivity observed with aryl-containing auxiliaries is attributed
to cation−π interactions between the Grignard dimer and the
auxiliary. While these synthons should be of broad synthetic
utility, they bear strong application in the preparation of 5,5-
disubstituted pyrrolopyrimidines and -pyrimidinones, a class of
bioactive molecules of considerable interest as exemplified by
Synthesis 2012, 44, 2396. (f) Day, J. E.; Frederickson, M.; Hogg, C.;
Johnson, C. N.; Meek, A.; Northern, J.; Reader, M.; Reid, G. Synlett
2015, 26, 2570. (g) Kokai, E.; Nagy, J.; Toth, T.; Kupai, J.; Huszthy,
P.; Simig, G.; Volk, B. Monatsh. Chem. 2016, 147, 767.
(3) Raghavan, S.; Stelmach, J. E.; Smith, C. J.; Li, H.; Whitehead, A.;
Waddell, S. T.; Chen, Y.-H.; Miao, S.; Ornoski, O. A.; Garfunkle, J.;
Liao, X.; Chang, J.; Han, X.; Guo, J.; Groeper, J. A.; Brockunier, L. L.;
Rosauer, K.; Parmee, E. R. PCT Int Appl WO 2011149921, 2011.
(4) See ref 1d and references cited therein.
(5) (a) Reekie, T. A.; Donckele, E. J.; Trapp, N.; Diederich, F. Eur. J.
Org. Chem. 2015, 2015, 7264 and references therein. (b) Hall, H. K.,
Jr.; Sentman, R. C. J. Org. Chem. 1982, 47, 4572. (c) Donckele, E. J.;
Reekie, T. A.; Trapp, N.; Diederich, F. Eur. J. Org. Chem. 2016, 2016,
716.
(6) Tyutin, V. Y.; Chkanikoc, N. D.; Kolomietz, A. F.; Fokin, A. V. J.
Fluorine Chem. 1991, 51, 323.
14.
ASSOCIATED CONTENT
Supporting Information
(7) For preparation of compound 5b, see: Yamada, Y.; Iguchi, K.;
Hosaka, K.; Hagiwara, K. Synthesis 1974, 1974, 669.
■
*
S
(8) (a) Formation of dimer of 5b was reported, but a structure was
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01930.
not proposed; see ref 7. (b) Formation of byproduct 6 was accelerated
when stored neat or at room temperature for prolonged periods of
time. Compound 5b was stored as a 1 M solution in benzene at −4 to
−
20 °C.
9) This selectivity trend is in line with previous reports of reactions
X-ray data for compound 14 (CIF)
Experimental details, characterization data, and NMR
spectra for all new compounds (PDF)
(
with substrate 5a in which the position β to the dinitrile appears to
react preferentially. See ref 5a,b.
(10) 5:1 α/β selectivity was observed; see the SI.
(
11) For an example of phenylcyclohexanol as a chiral ester
AUTHOR INFORMATION
Corresponding Authors
■
*
*
appendage on a kilogram scale, see: Song, J. J.; Tan, Z.; Xu, J.;
Reeves, J. T.; Yee, N. K.; Ramdas, R.; Gallou, F.; Kuznich, K.;
DeLattre, L.; Lee, H.; Feng, X.; Senanyake, C. H. J. Org. Chem. 2007,
72, 292.
E-mail: alan_whitehead@merck.com.
E-mail: yong_zhang@merck.com.
ORCID
(
12) SFC separation was used to prepare enantiomerically pure
auxiliaries, but chiral syntheses have been reported.
Alan Whitehead: 0000-0003-0908-846X
Edward C. Sherer: 0000-0001-8178-9186
Yu-hong Lam: 0000-0002-4946-1487
(13) 2-Substituted aryl analogues were prone to elimination during
ester formation step with the alcohol and phenylglyoxylic acid.
(
(
14) See the SI.
15) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J.
Notes
Phys. Chem. B 2011, 115, 14556.
The authors declare no competing financial interest.
(16) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(
b) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
009, 113, 6378.
17) The absolute stereochemistry of 12i was assigned according to
2
(
ACKNOWLEDGMENTS
■
We gratefully acknowledge Richard Ball (Merck & Co., Inc.)
and Andrew Brunskill (Merck & Co., Inc.) for X-ray
crystallography support for structure 14, Ryan Cohen (Merck
the known stereochemistry of 8c and 14. Both 12i and 8c→9e led to
the same enantiomer of 14.
(18) See the SI for details.
&
Co., Inc.) for NMR support for 6, and Leo Joyce (Merck &
(19) The absolute configuration of 14 was determined by X-ray
crystallography, and the enantiomer formed was evaluated by SFC
chiral chromatography; see the SI.
Co., Inc.) for VCD support for 8c. We also thank Jinchu Liu
(
Merck & Co., Inc.) for chiral SFC separations support.
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