Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates

Article abstract of DOI:10.1021/acs.orglett.6b00451

The poor regioselectivity of the [4 + 2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon-carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors.

Full text of DOI:10.1021/acs.orglett.6b00451

Letter
pubs.acs.org/OrgLett
Regioselective Synthesis of 3‑Hydroxy-4,5-alkyl-Substituted
Pyridines Using 1,3-Enynes as Alkynes Surrogates
†
†
‡
,†
Manuel Barday, Kelvin Y. T. Ho, Christopher T. Halsall, and Christophe Aïssa*
†
Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom
‡
Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
*
S Supporting Information
ABSTRACT: The poor regioselectivity of the [4 + 2] cyclo-
addition of 3-azetidinones with internal alkynes bearing two alkyl
substituents via nickel-catalyzed carbon−carbon activation is
addressed using 1,3-enynes as substrates. The judicious choice
of substitution on the enyne enables complementary access to
each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines,
which are important building blocks in medicinal chemistry
endeavors.
lkynes are prominent and versatile building blocks for the
as surrogates of alkynes that would otherwise be substituted
with two sterically similar alkyl chains R and R (Scheme 2).
1
2
A
synthesis of heterocycles by transition-metal-catalyzed
1
cycloadditions. However, poor regioselectivity is often
observed in these reactions for internal alkynes bearing two
alkyl substituents that are not electronically or sterically
Scheme 2. Strategy for the Regioselective Synthesis of 3-
Hydroxy-4,5-bisalkyl Pyridines
2
strongly biased. The nickel-catalyzed [4 + 2] cycloaddition
of N-Ts-3-azetidinone 1 (Ts = para-tolylsulfonyl) and alkyne 2
is a typical example illustrating the lack of selectivity when the
steric differentiation between the substituents on the alkyne
moiety is limited, and an almost equimolar mixture of the
regioisomers of dihydropyridinone 3 was thus obtained
3
(
Scheme 1). Initial attempts to improve the regioselectivity
by varying the ligand remained unsuccessful while the
conversion to the desired product decreased. Moreover, the
regioisomers could not be separated by simple column
chromatography.
We therefore decided to explore an alternative strategy
consisting of using the inexpensive ligand PPh and 1,3-enynes
3
Scheme 1. Poor Regioselectivity in the Nickel-Catalyzed [4 +
2
2
] Cycloaddition of N-Ts-3-azetidinone and 4-Methyl-pent-
-yne
The enhanced regioselectivity of the insertion of 1,3-enynes as
compared to internal alkynes bearing two alkyl substituents was
previously demonstrated for this reaction albeit with only one
a
3a,b
example,
but we assumed that this preliminary observation4
could be generalized to other enynes on the basis of theoretical
5
and experimental studies conducted on the related nickel-
catalyzed reductive coupling of 1,3-enynes with aldehydes. In a
sequence inspired by the work previously reported by Fagnou
and co-workers for the synthesis of 2,3-aliphatic-substituted
6
pyrroles and indoles, we envisioned that the judicious choice
a
The reactions were carried out with 1 (0.22 mmol) and 2 (0.24
of substitution on the 1,3-enyne would enable complementary
access to each of the two regioisomers of 3-hydroxy-4,5-alkyl-
substituted pyridines, after simple hydrogenation and aroma-
b
1
c
1
mmol). Conversion determined by H NMR. Determined by H
NMR of the crude mixture. Used as 1 M solution in THF. Made in
situ by premixing 1,3-bis(2,4,6-trimethylphenyl)-imidazolium chloride
d
e
f
(
20 mol %) and tBuOK (20 mol %). Extensive decomposition of 1
Received: February 16, 2016
was observed, and 3 was not formed.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00451
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
tization steps (Scheme 2). Pyridines that have a hydroxyl
group in position 3 and two different alkyl groups in positions 4
and 5 are found in compounds that display important biological
and pharmaceutical properties and are desirable building blocks
Table 1. Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-
Substituted Pyridines Using 1,3-Enynes as Alkynes
Surrogates
a
8
in medicinal chemistry endeavors. The strategy presented
herein offers a valuable alternative to previous approaches to
9
this specific pyridine motif and to metal-catalyzed intermo-
lecular reactions of alkynes that afford other pyridine
10
substitution patterns.
As expected, all 1,3-enynes 4a−4h underwent the nickel-
catalyzed [4 + 2] cycloaddition with good regioselectivity
(Table 1, entries 1−8), and the major regioisomer of 5 could be
isolated easily in most cases, except for 5b, which explains the
moderate yield for this specific example, as opposed to the
range of good yields observed for 5a and 5c−5h (67−77%).
Although the origin of this effect is not known to us, the
average yields of duplicate experiments were consistently higher
in some cases (entries 1−5) when the loading of PPh was
3
increased from 20 to 30 mol % (see Supporting Information).
Moreover, the directing power of the carbon−carbon double
bond of the 1,3-enyne motifs was slightly greater for 1,4-
disubstituted enynes (entries 2, 4, and 6−8) than for 2,4-
disubstituted (entry 3) or trisubstituted enynes (entries 1 and
5). Nevertheless, this directing effect persisted even with two
substituents of similar size on the carbon−carbon triple bond.
Thus, we observed a 78:22 regioselectivity for 1,3-enynes 4i
and 4j and the major regioisomer could be isolated in 65% and
6
4% yield, respectively (Scheme 3). The reaction of a mixture
of tri- and tetrasubstituted enynes 4k led to 5k in lower yield
but with good regioselectivity, an outcome likely influenced by
the steric properties of 4k. The substitution of the alkyl group
had a very limited effect on the regioselectivity (Table 1, entries
2
, 4, 6, and 8).
The conversion of dihydropyridinones 5a−5h into pyridines
a−6h was effected in two steps by hydrogenation of the
6
carbon−carbon double bond followed by cleavage of the para-
tolylsulfonyl group and concomitant aromatization using
9
b
DBU (Table 1). Thus, the judicious choice of 1,3-enynes
a−4h enabled a rapid three-step access to each of the two
regioisomers of 3-hydroxy-4,5-aliphatic-substituted pyridines
a/6b, 6c/6d, 6e/6f, and 6g/6h. It was possible to conduct the
4
6
deprotection/aromatization of compounds 5 prior to hydro-
genation, but the resulting pyridines were not suitable
substrates for hydrogenation and compounds 6 were thus not
obtained.
In addition, we also explored an alternative protocol whereby
the active Ni catalyst was generated in situ from air-stable
precatalyst NiBr (PPh ) and Zn. Although initial investigations
2
3 2
with 1,3-enyne 4l were promising, the major regioisomer 5l
being isolated in 67% yield (eq 1), yields were in general lower
a
All reactions were carried out with 1 (0.22 mmol), 4 (0.24 mmol),
Ni(cod) (0.022 mmol), and PPh (0.044 mmol) except otherwise
noted. Yield of the isolated major regioisomer only, average of two
2
3
b
c
d
1
experiments. 30 mol % PPh . From H NMR of the crude mixture.
3
e
f
Yield of isolated 6 after two steps. Hydrogenation was performed in a
g
flask immersed in a sonication bath for 5 h. Hydrogenation for 7.5 h.
h
Hydrogenation for 5 h.
from enynes 4a−4f when compared to the method relying on
14% yield (84:16 regioselectivity). A slightly improved result
was obtained by replacing the protective group in 1 with a tert-
butoxycarbamoyl group (27%; 90:10 regioselectivity).
Ni(cod) /PPh and the regioselectivity was slightly decreased
2
3
(Table 2). During the preparation of this manuscript, a report
disclosed that the combination of NiBr (PPh ) and Zn in
Initially, the cycloaddition of terminal 1,3-enyne 7 with 1 led
to a very sluggish reaction and only very low yields of
dihydropyridinone 8 (Table 3, entry 1). It was crucial to use
commercially available N-Boc-3-azetidinone 9 (Boc = tert-
2
3 2
MeCN enabled the [4 + 2] cycloaddition of alkynes and
11
protected azetidin-3-ones. However, using this solvent in the
case of 4l led to incomplete conversion and 5l was isolated in
B
DOI: 10.1021/acs.orglett.6b00451
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Reactions of Enynes 4i, 4j, and 4k
As previously demonstrated by our group and others, α-
substituted 3-azetidinones are good substrates for the [4 + 2]
3
Ni-catalyzed cycloadditions with alkynes. This remains true for
1
,3-enynes, as illustrated with 12 (Scheme 4), which is derived
Scheme 4. Reactions of N-Ts-2-benzyl-3-azetidinone 12
a
Same reaction conditions as those listed for Table 1 (entries 1−5).
a
Yield of isolated major regioisomer only, average of two experiments.
Yield of isolated product after two steps.
Table 2. Cycloaddition of N-Ts-3-Azetidinone with 1,3-
b
a
Enynes 4a−4f Catalyzed by NiBr (PPh ) /Zn
2
3 2
b
c
product
yield (%)
ratio of regioisomers
from racemic phenylalanine. The reaction of 4l with 12 was
slower than that with nonsubstituted 1, but 13 was easily
separated from its regioisomer in 64% yield (91:9 regiose-
lectivity). Then, 13 could be rapidly converted into 14 in good
yield after hydrogenation followed by cleavage of the para-
tolylsulfonyl group and concomitant aromatization using
5a
5b
5c
5d
5e
5f
66
31
51
59
69
50
85:15
91:9
85:15
91:9
87:13
91:9
NaHCO in a mixture of ethanol and water as an alternative
3
a
b
to DBU.
Reaction conditions are same as those in eq 1. Yield of the isolated
major regioisomer. From H NMR of the crude mixture.
c
1
Although it would in principle be possible to access
analogues of 14 from various α-substituted 3-azetidinones, it
is more judicious to postpone the functionalization of 3-
hydroxy-4,5-alkyl-substituted pyridines at a later stage of the
sequence. For example, dihydropyridinone 5l was obtained in
good yield after treating a mixture of 1 and 4l with 5 mol % of
catalyst and separation of the regioisomers (Scheme 5). Then,
hydrogenation and cleavage of the para-tolylsulfonyl group with
concomitant aromatization gave 15 in 73% over two steps. At
this stage, a Mannich reaction with either morpholine or
pyrrolidine afforded 2-aminomethylpyridine derivatives 16 and
Table 3. Nickel-Catalyzed Cycloaddition of 3-Azetidinones
a
with a Terminal 1,3-Enyne
b
entry
1 or 9
solvent
temp (°C)
t (h)
yield (%)
Scheme 5. Further Functionalization of 3-Hydroxy-4-ethyl-5-
isopropylpyridine 15
1
2
3
4
5
1
9
9
9
9
toluene
toluene
THF
60
60
60
60
70
144
40
40
16
16
7
40
35
c
dioxane
dioxane
58
41
a
All reactions were carried out with 1 or 9 (0.22 mmol), 7 (0.24
b
mmol), Ni(cod) (0.022 mmol), and PPh (0.066 mmol). Yield of
isolated 8 (entry 1) or 10 (entries 2−5). Average of two experiments.
2
3
c
butoxycarbamoyl) instead of N-Ts-3-azetidinone 1 and to use
dioxane as solvent (entries 2−4) in order to obtain compound
10 in good yield. Increasing the reaction temperature was not
beneficial (entry 5). Importantly, only one regioisomer of 10
was observed. Similarly to 5a−5h, compound 10 could be
conveniently converted into 3-hydroxy-pyridine 11 in a few
steps (eq 2). A single purification by column chromatography
was necessary at the end of this sequence, and compound 11
was isolated in 57% yield.
a
b
Yield of isolated major regioisomer only. Ratio of regioisomer in the
crude reaction mixture.
C
DOI: 10.1021/acs.orglett.6b00451
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
7 in excellent yields. Alternatively, 15 could be converted
Letter
12
1
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into 18, which led to furo[b]pyridine derivative 19 after a
13
Sonogashira cross-coupling.
In conclusion, we have demonstrated that 1,3-enynes are
convenient surrogates of internal alkynes bearing two alkyl
substituents in their nickel-catalyzed [4 + 2] cycloaddition with
3
-azetidinones. Thus, the judicious choice of 1,3-enyne pairs
2
(
012012478A1.
enables a facile and complementary access to each of the two
regioisomers of 3-hydroxy-4,5-alkyl-substituted pyridines, after
simple hydrogenation and aromatization steps.
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■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00451.
(10) Selected examples: (a) Roesch, K. R.; Larock, R. C. J. Org. Chem.
Detailed experimental procedures and characterization of
all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
J.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002,
■
*
6
8
2
́
7, 4414. (e) Varela, J. A.; Castedo, L.; Saa, C. J. Org. Chem. 2003, 68,
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E-mail: aissa@liverpool.ac.uk.
Notes
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H. Org. Lett. 2008, 10, 325. (i) Colby, D. A.; Bergman, R. G.; Ellman,
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H. Chem. Commun. 2012, 48, 8105. (m) Kim, D.-S.; Park, J.-W.; Jun,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from EPSRC (EP/
P505615/1 studentship to K.Y.T.H.), the University of
Liverpool (Studentship to M.B.), and AstraZeneca.
(o) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012,
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DOI: 10.1021/acs.orglett.6b00451
Org. Lett. XXXX, XXX, XXX−XXX