Regioselective nucleophilic addition of organometallic reagents to 3-geminal bis(silyl) N-acyl pyridinium

Article abstract of DOI:10.1021/ol500302r

A regioselective nucleophilic addition to 3-geminal bis(silyl) N-acyl pyridinium has been described. Geminal bis(silane) shows contrasting roles that lead to different regioselectivities for the addition of different nucleophiles: its steric effect dominates to favor 1,6-addition of alkyl, vinyl, and aryl organometallic reagents; its directing effect dominates to favor 1,2-addition of less sterically demanding alkynyl Grignard reagents.

Full text of DOI:10.1021/ol500302r

Letter
pubs.acs.org/OrgLett
Regioselective Nucleophilic Addition of Organometallic Reagents to
3‑Geminal Bis(silyl) N‑Acyl Pyridinium
Ya Wu,† Linjie Li,† Hongze Li,† Lu Gao,† Hengmu Xie,† Zhigao Zhang,† Zhishan Su,§ Changwei Hu,*,§
and Zhenlei Song*,†,‡
†Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
§
‡State Key Laboratory of Biotherapy, West China Hospital, Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu 610041, P. R. China
S
* Supporting Information
ABSTRACT: A regioselective nucleophilic addition to 3-geminal bis(silyl) N-acyl pyridinium has been described. Geminal
bis(silane) shows contrasting roles that lead to different regioselectivities for the addition of different nucleophiles: its steric effect
dominates to favor 1,6-addition of alkyl, vinyl, and aryl organometallic reagents; its directing effect dominates to favor 1,2-
addition of less sterically demanding alkynyl Grignard reagents.
effect”.5 On the other hand, trialkyltin and trialkylsilyl groups at
ucleophilic addition of organometallic reagents to N-acyl
1
Npyridinium species
the 3-position effectively block both C-2 and C-4, and this so-
called “steric effect” favors 1,6-addition, as Comins elegantly
showed.6
is one of the most widely used
protocols to functionalize pyridine. The dihydropyridines so
generated can be transformed by reduction into tetrahydropyr-
idines and piperidines or by oxidation into substituted
pyridines.2 All these heterocycles are important building blocks
in the synthesis of biologically active molecules.3
When N-acyl pryridinium contains a 3-substituent, the
addition of hard nucleophiles such as Grignard reagents
generally proceeds through either a 1,2- or 1,6-pathway
(Scheme 1, top). The regioselectivity usually depends on the
nature of the 3-substituent. Methyl, methoxy, or halogen
groups at the 3-position favor 1,2-addition as a result of the so-
called “directing effect”.4 Charette recently reported that such a
1,2-regioselectivity can be even enhanced by utilizing an
imidate as the N-activating group to provide an extra “directing
We recently embarked on a series of investigations into
geminal bis(silanes),7 in which two silyl groups are attached to
one carbon center. In the course of this work, we discovered
that geminal bis(silane) in the 3-position of N-acyl pyridinium
exerted contrasting effects on the regioselectivity of nucleo-
philic addition (Scheme 1, bottom). In additions involving
alkyl, vinyl, and aryl Grignard reagents, the bulkiness of the
geminal bis(silyl) group imposes a strong steric effect that
shields both C-2 and C-4, selectively promoting 1,6-addition. In
additions involving less sterically demanding alkynyl Grignard
reagents, geminal bis(silane) exerts a directing effect that favors
1,2-addition. Donohoe recently observed a contrasting
regioselectivity in the addition of Grignard reagents to 4-
methoxy methyl picolinate-derived N-alkyl pryridinium. The
discrepancy was rationalized by the hard/soft acid/base
(HSAB) model based on the different charge distribution at
the C-2 and C-6 centers.8 Here we describe detailed studies of
our reaction.
Scheme 1. General Description of 1,2- and 1,6-Addition to
3-Substituted N-Acyl Pyridinium (Top); Geminal
Bis(silane)-Controlled Addition with Divergent
Regioselectivity (Bottom)
First we examined the reaction using geminal bis(trimethyl-
silyl)-substituted pyridine 1 as a model scaffold, which was
prepared in 80% yield via Kumada coupling of (Si-
Me3)2CHMgCl and 3-bromopyridine. Acylation of 1 with i-
PrCOCl in THF at −78 °C generated the corresponding
pyridinium. Subsequent addition by EtMgBr afforded 1,6-
adduct 2a in 45% yield as a major regioisomer, which was
Received: January 28, 2014
Published: March 25, 2014
© 2014 American Chemical Society
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Letter
contaminated with 1,2- and 1,4-adducts in a ratio of 82:8:10
(Table 1, entry 1). We attributed the moderate yield to
harder vinyl and aryl ones (entries 4−7). Nevertheless, (E)-zinc
enolate derived from 3-pentanone, which is softer than
organomagnesium, underwent predominantly 1,6-addition
(1,6-/1,4- = 90:10) to give 2i in 80% yield as a single syn-
isomer.10 However, addition of the even softer (n- Bu)2CuLi
favored the 1,4-pathway to afford 2j in 35% yield.
a
Table 1. Screening of Reaction Conditions
This addition also proved applicable to pyridiniums derived
from 1 using various activating reagents, including unbranched
alkyl acyl chloride substituted with olefin and halides (Table 3,
b
i-PrCOCl
(equiv)
EtMgBr
(equiv)
yield
Table 3. Scope of Activating Reagents for 1,6-Addition
c
entry
t (°C)
(2a)
2a/3/4
1
2
1.3
2.0
4.0
4.0
4.0
1.3
2.0
4.0
4.0
4.0
−78
−78
−78
−40
0
45%
51%
72%
65%
57%
82:8:10
80:8:12
a
3
78:7:15
72:9:19
68:11:21
4
5
a
b
Reaction conditions: 0.21 mmol of 1 and 0.84 mmol of i-PrCOCl in
entry
R1COCl
product
yield
0.8 mL of THF at −78 °C; then 0.84 mmol of EtMgBr for 30 min.
1
2
3
4
5
CH2CH(CH2)2COCl
Br(CH2)2COCl
ClCH2COCl
2k
2l
45%
51%
72%
65%
57%
b
Isolated yields after purification by silica gel column chromatography.
c
1
Ratios were determined by H NMR spectroscopy.
2m
2n
2o
PivCOCl
EtOCOCl
incomplete conversion of 1 under these reaction conditions.
Consistent with this idea, a higher yield of 72% was obtained by
increasing the loading of both i-PrCOCl and EtMgBr to 4.0
equiv (entry 3),9 although this also decreased regioselectivity
slightly to 78:7:15. The reaction temperature strongly affected
regioselectivity, with higher temperatures leading to lower 1,6-
regioselectivity (entries 3−5).
This approach proved applicable to a range of alkyl, vinyl,
and aryl Grignard reagents; the desired 1,6-adducts 2b−2h
were obtained in good yields with high regioselectivity. While
no 1,2-adducts were observed, 1,4-adducts were detected in
some cases (Table 2, entries 1−4). In general, the ratio of 1,6-
to 1,4-addition increased as the nucleophiles became bulkier
(entries 1−5). The ratio of 1,6- to 1,4-addition also increased
when switching from alkyl Grignard reagents (entries 1−3) to
a
b
1
Ratios were determined by H NMR spectroscopy. Isolated yields
after purification by silica gel column chromatography.
entries 1−3), bulky pivaloyl chloride (entry 4), and ethyl
chloroformate (entry 5). Complete 1,6-regioselectivity was
observed in all these cases. The adducts 2k and 2l possess the
potential for subsequent intramolecular transformations, such
as a Diels−Alder reaction of 2k and radical cyclization of 2l.
Next we tested the addition of EtMgBr to 5-methyl-
substituted geminal bis(silyl) pyridine 5. Surprisingly, the
addition gave 6 in 63% yield with an even higher ratio of 1,6- to
1,2-adduct (90:0) than the addition using compound 1 without
a 5-substituent (78:7), even though the C-6 of 5 is more
crowded (Scheme 2). NOE experiments of 1 revealed an
approximately 1:3 equilibrium of conformers 1-Con-A and 1-
Con-B.11 While both conformers favor 1,6-addition, it seems
reasonable that 1-Con-B would undergo 1,2-addition to some
extent because the geminal bis(silane) shields the C-2 less
effectively than it does in 1-Con-A. NOE analysis of 5 showed
an approximately 1:1 equilibrium of 5-Con- A and 5-Con-B.12
Table 2. Scope of Organometallic Reagents for 1,6-Addition
Scheme 2. Comparing the 1,6-Regioselectivity in the
Formation of 6 and 2a
a
Isolated yields after purification by silica gel column chromatography.
Ratios were determined by H NMR spectroscopy.
b
1
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Letter
The 1,2-pathway of addition should be even more unfavorable
for 5-Con-B than for 1-Con-B, since the directing effect from
5-Me should provide extra driving force favoring 1,6-addition.
When mono-SiMe3-substituted pyridine 7 was reacted with i-
PrCOCl and EtMgBr, 8-[1,6], 8-[1,2], and 8-[1,4] were
obtained in an overall yield of 94% and in a ratio of 14:42:44
(Scheme 3). This contrasts with the ratio of 78:7:15 in the
the 1,6-transition state, which would explain the observed
preference for 1,2-addition. The hypothesis was further
supported by the results from DFT calculation at the
B3LYP/6-311++G**(PCM, THF) //B3LYP/6-311G** level,
which shows that 1,2-adduct 9 is energetically more stable than
1,6-adduct 10 by 1.62 kcal/mol.
The geminal bis(silyl) group in 2b was subjected to
transformations into other useful functionalities (Scheme 5).
Scheme 3. Reaction of Mono-SiMe3-Substituted Pyridine 7
Scheme 5. Functionalization of 2b
formation of 2a. Such a large difference in regioselectivity
suggests that the unique steric effect of geminal bis(silane) is a
crucial driver in the preference for 1,6-addition to 1.
We were surprised to find that using harder and less sterically
demanding alkynyl Grignard reagents switched the regiose-
lectivity of addition from the 1,6- to 1,2-pathway (Scheme 4).
Removing two silyl groups with TBAF provided 3-methyl
dihydropyridine 11 in 92% yield, while desilylation and
Peterson olefination with formaldehyde afforded 12 containing
a 3-vinyl group in 50% yield. Double oxidation16 of the
dihydropyridine and geminal bis(silane) with CAN generated
13 in 50% yield. Partially hydrogenating 2b to generate
tetrahydropyridine and then oxidizing it with CAN gave 14 in
an overall yield of 60%.
Scheme 4. 1,2-Addition of Alkynyl Grignard Reagents to 1
In summary, we have described a regioselective nucleophilic
addition of organometallic reagents to 3-geminal bis(silyl) N-
acyl pyridinium. While the steric effect of geminal bis(silane)
favors 1,6-addition of alkyl, vinyl, and aryl organomagnesiums,
the directing effect favors 1,2-addition of alkynyl Grignard
reagents. Further applications of this methodology are currently
underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectra data for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
In these reactions, the 3-geminal bis(silane) behaves more like a
methyl group than a bulky silyl group. In other words, the silyl
group’s directing effect becomes more dominant than its steric
effect, favoring addition to the more crowded C-2. We
rationalize this directing effect according to Sundberg’s
proposal that transition states in the addition of small
nucleophiles possess a product-like character that reflects the
stability of the products.13 The 1,2-adduct 9 should be more
stable than the 1,6-adduct 10 because 9 features a diene
containing a terminal-substituted geminal bis(silane). This
bis(silane) acts as a donor substituent due to the double
hyperconjugation effect between the two C−Si bonds and the
C−C double bond.14 Such a normal π-system should be more
stable than the iso π-system embedded in 10.15 A second line of
reasoning similarly suggests that 9 should be more stable: 10
probably suffers 1,3-allylic strain between H2 and H3′, while
such an interaction does not exist in 9 because the H2 is
oriented pseudoequatorially. Therefore both arguments predict
the 1,2-adduct to be more stable than the 1,6-adduct, implying
by extension that the 1,2-transition state is more favorable than
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: changweihu@scu.educn.
*E-mail: zhenleisong@scu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC
( 2 1 1 7 2 1 5 0 , 2 1 3 2 1 0 6 1 , 2 1 2 9 0 1 8 0 ) , N B R P C
(2010CB833200), and NCET (12SCU-NCET-12-03).
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