Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model

Article abstract of DOI:10.1038/nchem.1504

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle.

Full text of DOI:10.1038/nchem.1504

ARTICLES
PUBLISHED ONLINE: 25 NOVEMBER 2012 | DOI: 10.1038/NCHEM.1504
Regioselective reactions of 3,4-pyridynes enabled
by the aryne distortion model
Adam E. Goetz and Neil K. Garg
*
The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently
marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means
to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne
intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a
lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of
proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in
nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring
directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology
now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the
medicinally privileged pyridine heterocycle.
`
he pyridine ring is one of the most important heterocycles in † Caubere and co-workers found that oxygen and nitrogen substitu-
drug discovery1,2. It is present in more than 100 currently mar-
keted drugs, including the blockbuster drugs esomeprazole
ents positioned in close proximity to the 3,4-pyridyne could also
lead to enhanced selectivity for the addition of amines19. For
example, treatment of halopyridine 6 with diethylamine under
NaNH2/NaO-t-Bu conditions gave 8 in 80% yield, along with
10% of the C3 isomer, both presumably arising via pyridyne 7.
´
T
(Nexium) and loratadine (Claritin), in addition to the recently
approved cancer therapeutic crizotinib (Xalkori) (Fig. 1a). Other
drugs that contain the pyridine ring, or some derivative thereof,
include the life-changing medicines montelukast sodium (Singulair, † Guitian examined the influence of C2 halide substituents, which
for asthma/allergies), pioglitazone (Actos, for diabetes), eszopiclone
(Lunesta, for insomnia), imatinib mesylate (Gleevec, for various
cancers), lansoprazole (Prevacid, for acid reflux/ulcers) and mirtaza-
pine (for depression). As a result of the immense value of pyridines,
for decades methods to access functionalized derivatives of this privi-
leged heterocycle have been highly sought1. Several elegant methods
could be removed later, on the 3,4-pyridyne for use in a cyclo-
addition with substituted furans, which has applications in
the synthesis of the natural product ellipticine12,13. Although
bromide and fluoride groups did not significantly influence
regioselectivity, some success was achieved using a C2 chlorosub-
stituent (9 þ 10 ꢀ 11 þ 12). Interestingly, the authors reported
that the presence of a chloride at C5 of the 3,4-pyridyne gave an
equimolar mixture of cycloadducts using furan 9.
were reported recently for the assembly of substituted pyridines3–6
.
A promising approach towards polyfunctionalized pyridines
involves the use of highly reactive pyridyne intermediates7–23, such
as the isomeric hetarynes 1 and 2 (Fig. 1b), which are valued for
their electrophilicity and high reactivity towards nucleophiles and
cycloaddition partners24,25. The first pyridyne studies were reported
in 1955, with Levine and Leake’s seminal discovery of 3,4-pyridyne
(2) (ref. 7). Despite the many studies that followed over the sub-
sequent 50 years, pyridynes have yet to mature into a widely used
tool for the assembly of functionalized pyridine scaffolds. The 2,3-
pyridyne (1) reacts with excellent degrees of regioselectivity to give
2-substituted pyridines or related cycloadducts20,21; however, other
methods for C2 functionalization of pyridines are available and are
often preferred1. In the case of 3,4-pyridynes (for example, 2), nucleo-
philic additions are known to occur without significant selectivity for
attack at either C3 or C4 (refs 9–19). If the regioselectivity in reactions
of 3,4-pyridynes could be controlled, these intermediates could serve
as valuable building blocks for the synthesis of substituted pyridines
that are otherwise difficult to access.
The studies highlighted in Fig. 1 demonstrate that substituent
effects can modulate pyridyne regioselectivities, particularly for
the favoured addition at C4. However, subsequently the ability to
manipulate or remove the C2 amide-, oxygen- or nitrogen-directing
groups of Snieckus’ and Caubere’s work is limited. Guitian’s use of
neighbouring halides to modulate 3,4-pyridyne regioselectivity
gave mixed results, with a C2 chloride being the most promising
directing group for the specific cycloaddition examined.
Moreover, the most well-studied examples of regioselective
3,4-pyridyne reactions are restricted to the use of amine- or
alcohol-based nucleophiles, and various other trapping agents
have yet to be explored.
Herein we report the design and synthesis of substituted 3,4-
pyridynes that react with significant regioselectivities. Our strategy
renders 3,4-pyridynes synthetically useful for the assembly of
highly functionalized pyridine scaffolds and features several key
design elements:
`
´
Prior efforts to modulate regioselectivities of 3,4-pyridynes using
substituent effects were met with promising results and can be
summarized as follows (Fig. 1c–e):
† The pyridynes are accessed from pyridylsilyltriflate precursors
using mild fluoride-based reaction conditions. This allows for a
broad range of trapping agents (nucleophiles and cycloaddition
partners) to be employed, which in turn delivers a more
diverse collection of polysubstituted pyridine derivatives.
† Snieckus and co-workers reported a single example using a C2
amido group to enhance nucleophilic addition to C4 of a
3,4-pyridyne intermediate (3 ꢀ 4 ꢀ 5) (ref. 18).
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA. e-mail: neilgarg@chem.ucla.edu
*
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.
1

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1504
ARTICLES
in conjunction with modern Ni-catalysed cross-couplings offer
an effective new means to access functionalized pyridines.
a
HN
OMe
Cl
F
Me
Me
N
O
Cl
The methodologies reported herein now render 3,4-pyridynes
broadly useful as tools for the construction of polysubstituted pyri-
dines. We expect our findings will promote the use of 3,4-pyridynes
and other heterocyclic arynes in the synthesis of medicinally privi-
leged molecular scaffolds.
N
S
N
N
N
O
HN
N
Me Cl
NH2
O
N
EtO
OMe
Esomeprazole
(Nexium)
Loratadine
(Claritin)
Crizotinib
(Xalkori)
Results and discussion
Treatment of acid
reflux
Treatment of
allergies
Treatment of lung
cancer
Design and synthesis of pyridyne precursors. The observation that
3,4-pyridyne 2 reacts with poor regioselectivity can be explained by
consideration of the aryne distortion model26–28. The geometry-
optimized structure of 2 obtained from density functional theory
(DFT) calculations (B3LYP/6-31G*) (ref. 29) is shown in Fig. 1b.
Pyridyne 2 possesses only minor aryne distortion, as evidenced
by the nearly identical internal angles at C3 and C4. We
hypothesized that neighbouring electron-withdrawing substituents
at C5 or C2 could increase the aryne distortion, and thus provide
4
b
c
3
3
125.3º
124.7º
2
N
N
2,3-pyridyne (1)
3,4-pyridyne (2)
Reacts regioselectively
(attack at C2)
Reacts with poor regioselectivity
(slight preference, attack at C4)
more degrees of regioselectivity.
12,13
´
Bearing in mind the seminal findings of Guitian
and that
TES
SPh
4
4
PhSH
TBAF
3
aryne distortion and subsequent regioselectivities may be perturbed
by inductively electron-withdrawing substituents24,30, we evaluated
a series of 2- and 5-substituted 3,4-pyridynes using computational
methods (Fig. 2; also see Supplementary Fig. S2). Parent pyridynes
have been studied computationally31, but no calculations that
involve C2- or C5-substituted derivatives are available in the litera-
ture. We considered chloride, bromide, iodide and sulfamate substi-
tuents to be particularly attractive pyridyne substituents, as each
could plausibly serve as a handle for further elaboration after
being used to modulate pyridyne regioselectivity. Although less
useful synthetically, the methoxy substituent was also evaluated as
a point of comparison, because the methoxy group is well-known
to govern regioselectivity in reactions of benzyne through significant
aryne distortion24.
OTf
NEt2
2
NEt2
NEt2
N
N
N
MeCN, 0 ºC
(55% yield)
O
O
O
3
4
5
d
e
4
NEt2
Br
NaNH2/NaO-t-Bu
3
4
3
HNEt2
(10% C3 isomer
also observed)
OEt
2
N
OEt
N
OEt
THF, 20 ºC
(80% yield)
N
6
7
8
PhO2S
N
Me
PhO2S
As summarized in Fig. 2, computations predict that a variety
of electron-withdrawing substituents could be used to induce 3,4-
pyridyne distortion. In the case of 5-substituted pyridynes, the
inductively withdrawing substituents cause a flattening at C3,
which, according to the aryne distortion model, suggests this
would be the preferred site of attack by nucleophiles26.
Specifically, the more linear terminus of the aryne possesses a
greater p character and is therefore more electropositive. A similar
effect was seen in our studies of 2-substituted 3,4-pyridynes. In all
cases, the electron-withdrawing substituents lead to a flattening at
C4, which is in turn predicted to be the preferred site of attack
by nucleophiles.
The aryne distortion model suggests that arynes with internal
angle differences ≥48 should react with significant regioselectivities
in nucleophilic addition and cycloaddition reations26. As the sub-
stituted 3,4-pyridynes shown in Fig. 2a all meet this criterion and
their distortions are generally on par with those of methoxy-
substituted pyridynes, we hypothesized that any of the halo- or
sulfamoylpyridynes would prove useful. We envisioned accessing
pyridynes from silyltriflate precursors, as aryne formation would
be achieved readily using mild fluoride-based conditions. In
addition, this general method (that is, the Kobayashi approach to
aryne generation)32 was expected to be highly tolerant of an array
N
O
9
N
Me
Me
SO2Ph
Me
+
O
O
4
CsF
+
Me
Me
TMS
3
MeCN
OTf
X
N
X
N
X
11a–11c
12a–12c
2
N
10a X = Cl
10b X = Br
10c X = F
11a:12a = 2.4:1 (88% yield)
11b:12b = 1:1 (40% yield)
11c:12c = 1.1:1 (38% yield)
Figure 1 | Pyridine-containing drugs, pyridyne isomers and previous
examples of pyridynes. a, Common pharmaceutical drugs that contain the
pyridine scaffold. b, The structure of 2,3-pyridyne (1) and energy-minimized
structure of 3,4-pyridyne (2) obtained using B3LYP/6-31G* calculations.
The lack of unsymmetrical aryne distortion is responsible for the poor
regioselectivity in the reactions of 2. c, Snieckus’ use of a C2 amide to direct
`
an attack at C4 of pyridyne 4. d, Caubere’s use of a C2 oxygen substituent
´
in the dehydrohalogenation approach to pyridyne 7. e, Guitian’s examination
of the effects of halides on pyridyne cycloadditions. TES ¼ triethylsilyl,
Tf ¼ trifluoromethanesulfonyl, TBAF ¼ tetra-N-butylammonium fluoride,
THF ¼ tetrahydrofuran.
† A C5-bromide substituent is used to induce aryne distortion of functional groups and trapping agents, and therefore could be
and direct nucleophilic additions to C3 of 3,4-pyridynes. used in a range of aryne-trapping processes24.
Subsequently, the bromide may be manipulated using conven-
tional Pd-catalysed reactions.
Figure 2b summarizes several key aspects of pyridyne design that
were considered prior to the synthesis of substituted pyridynes.
† By positioning a sulfamoyl group at C2 of the 3,4-pyridyne, With respect to the 5-substituted 3,4-pyridyne, bromopyridyne 13
aryne distortion is perturbed to favour attack at C4 of was considered attractive because the bromide induced considerable
3,4-pyridynes. Sulfamoyl groups have not been used previously pyridyne distortion and offered the most versatility for functionali-
to govern pyridyne or aryne regioselectivities, but when used zation after pyridyne trapping. Furthermore, the presumed
2
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1504
ARTICLES
a
b
4
4
5-Substituted 3,4-pyridynes
X
3
2
2-Substituted
3,4-pyridynes
3
5-Substituted
3,4-pyridynes
5
TMS
N
Br
N
X
Br
OH
Br
OTf
OTf
N
Difference
Difference
C3
C4
X
C3
C4
N
X
N
14
13
Cl
Br
121.8º
122.1º
127.6º
127.2º
5.8º
5.1º
Cl
Br
129.8º
129.1º
119.8º
120.6º
10.0º
8.5º
Readily available
TMS
N
R1O
5
R1O
HO
OH
I
123.3º
120.3º
121.6º
126.3º
128.9º
128.1º
3.0º
8.6º
6.5º
I
127.1º
130.5º
131.9º
122.8º
118.8º
118.3º
4.3º
11.7º
13.6º
OSO2NMe2
OMe
N
N
OSO2NMe2
OMe
15
Not readily
available
Attack at C3 favoured
Attack at C4 favoured
2-Substituted 3,4-pyridynes
c
TMS
OH
O
OTf
OR1
129º
Predicted site
of attack
121º
129º
120º
2
N
OR1
N
N
H
16
17
Readily available
13
16
Figure 2 | Design of 3,4-pyridynes with controllable regioselectivity. a, Effect of substituents at either C2 or C5 on the distortion of 3,4-pyridyne. Inductively
withdrawing substituents at C2 lead to a flattening at C4, but inductively withdrawing substituents at C5 lead to a flattening at C3. b, Selection of pyridyne
targets based on retrosynthetic analysis. c, Geometry-optimized structures of pyridynes 13 and 16 using B3LYP/6-31G* calculations and their predicted site of
attack based on the calculated angles. R1 ¼ SO2NMe2.
silyltriflate precursor to 13 would probably be accessible from the bromohydroxypyridine 14, although the conversion of 21 into 22
commercially available bromohydroxypyridine 14. 5-Sulfamoyl- required the use of a highly optimized two-step procedure.
3,4-pyridyne (15) was also attractive because computations Finally, silyltriflate 25 was synthesized from the known benzylether
suggested this species would be highly distorted. However, the pre- 23 (see Supplementary Information) using an efficient four-
sumed silyltriflate precursor to 15 did not appear readily accessible, step sequence that involved sulfamoylation and C4 silylation (23
because its probable predecessor, 3,5-dihydroxypyridine, is not ꢀ 24), followed by deprotection and triflation (24 ꢀ 25). Using
obtained easily. Regarding 2-substituted 3,4-pyridynes, the sulfa- these practical routes, gram quantities of silyltriflates 20, 22 and
mate was predicted to induce the greatest degree of distortion. 25 are readily accessible.
Coupled with the notion that it was plausible for an appropriate
Nucleophilic additions and cycloaddition reactions of 3,4-
pyridynes. To assess the influence of the C5 bromide substituent
silyltriflate to be accessed from commercially available dihydroxy-
pyridine 17, 2-sulfamoylpyridyne 16 was deemed an appropriate
target. Previously, sulfamates had not been used to direct aryne
regioselectivities, but success with them would offer a valuable
means to functionalize the pyridine ring after an aryne reaction
by exploiting modern Ni-catalysed coupling methodologies33.
Similarly, as demonstrated herein, the bromide of pyridyne adducts
may be manipulated strategically using conventional Pd-mediated
transformations. Geometry-optimized structures of pyridyne targets
13 and 16, obtained using DFT methods, are shown in Fig. 2c.
Robust syntheses of pyridylsilyltriflates 20, 22 and 25 were
developed, as these compounds were expected to function as
appropriate precursors to pyridynes 2, 13 and 16, respectively
(Fig. 3). Starting from commercially available 3-hydroxypyridine
(18), carbamoylation followed by a C4-selective o-lithiation gave
silylcarbamate 19 in 74% yield over two steps. A subsequent
one-pot deprotection/triflation protocol27 afforded silyltriflate 20.
This straightforward sequence provided the desired precursor to
3,4-pyridyne (2) in three steps and in .50% overall yield.
Although regioselectivities in reactions of unsymmetrical arynes
are not thought to be dependent on the isomer of silyltriflate
employed27,34–38, extensive efforts were made to synthesize the
regioisomer of precursor 20, in which the positions of the triflate
a
TMS
TMS
i. n-BuLi, Et2NH,
THF, –78 ºC
1. i-PrNCO, CH2Cl2, NEt3
OR2
OH
OTf
ii. PhNTf2,
–78 to 23 ºC
2.i. TMEDA, TBSOTf,
THF, –78 to 23 °C
ii. TMEDA, TMSCI, –78 ºC
N
N
N
(79% yield)
18
iii. LDA, –78 ºC
19
20
(74% yield, two steps)
b
Br
i. n-HexMgCl/
Et2NH, THF,
TMS
TMS
OH
1. i-PrNCO, CH2Cl2, NEt3
Br
OR2
Br
OTf
–78 ºC
2.i. TMEDA, TBSOTf,
N
ii. Tf2O, pyridine,
CH2Cl2,
–40 to 0 ºC
N
N
THF/Et2O, –78 to 23 ºC
ii. TMEDA, LDA, –78 ºC
iii. TMSCl, –78 ºC
14
21
22
(56% yield, two steps)
(53% yield, two steps)
c
TMS
i. ClSO2NMe2, NEt3,
PhMe, 110 ºC
TMS
OBn
OBn
OR1
OTf
i. H2, Pd/C, EtOAc
N
O
ii. n-BuLi, Tf2O,
Et2O, –78 ºC
ii. n-BuLi, TMSCl,
THF, –78 ºC
N
N
OR1
H
23
24
25
(80% yield, two steps)
(64% yield, two steps)
and trimethylsilyl (TMS) groups are reversed. However, in accord Figure 3 | Synthesis of silyltriflates 20, 22 and 25. a, Preparation of the
with a previous report, we were unable to prepare this compound, 3,4-pyridyne precursor 20. b, Preparation of the 5-bromo-3,4-pyridyne
presumably because of its instability39 and the lability of C4–OR precursor 22. c, Preparation of the 2-sulfamoyl-3,4-pyridyne precursor 25.
derivatives needed in our routes (for example, R ¼ TMS, R1 ¼ SO2NMe2, R2 ¼ C(O)NH-i-Pr, i-PrNCO ¼ isopropyl isocyanate,
C(O)NH-i-Pr) (refs 40,41). Bromosilyltriflate 22 was synthesized TMEDA ¼ N,N,N′,N′-tetramethylethane-1,2-diamine, TBS ¼ t-butyldimethylsilyl,
using an analogous route starting from the commercially available LDA ¼ lithium diisopropylamide, Pd/C ¼ palladium on carbon, Hex ¼ hexyl.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
3
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1504
ARTICLES
on 3,4-pyridyne regioselectivities, a comparative study that involved Table 1) were used to trap 13, ratios of the products obtained were
pyridynes 2 and 13 was undertaken (Table 1). Consistent with 3.3:1 and 1.7:1, respectively, with C3 being favoured in both cases.
computations and previous studies of 3,4-pyridynes, reactions that In the latter two cycloaddition reactions, the major products
involved 2 proceeded with modest regioselectivity across a range presumably arise from transition states that possess significant
of nucleophilic trapping agents42 and cycloaddition partners steric encumbrances. Consequently, the bromine’s influence on
(entries 1, 3, 5, 7 and 9, Table 1). Nucleophilic addition at C4 was aryne distortion and regioselectivity is thought to arise from
slightly favoured in all cases. In comparison, reactions of 5- electronic considerations rather than from steric factors.
bromo-3,4-pyridyne (13) uniformly gave improved degrees of
To further probe this notion, we compared bromopyridyne
regioselectivity with a reversal in selectivity that favoured the 13 with its 5-chloro analogue. Despite a previous example in
addition at C3. Use of N-methylaniline gave a mixture of C3 and which a 5-Cl substituent minimally perturbed regioselectivity in a
C4 adducts in a 5.8:1 ratio (entry 2, Table 1). Similarly, a 2.9:1 3,4-pyridyne cycloaddition13, we found that the chloride governed
ratio of adducts, which again favoured C3, was obtained when regioselectivities in reactions with morpholine and N-t-butyl-a-
morpholine was employed as the trapping reagent (entry 4, phenylnitrone (see Supplementary Fig. S1). Selectivities were
Table 1). Several formal cycloadditions were also tested. Whereas found to be more pronounced compared with those seen in
unsubstituted pyridyne
imidazolidinone (DMI)36 to give a 2.1:1 mixture of isomeric predictions shown in Fig. 2a based on the aryne distortion model.
products that favoured C4 addition (entry 5, Table 1), the use of Sulfamoylpyridyne 16 was next tested in nucleophilic additions
2
reacted with 1,3-dimethyl-2- reactions with bromopyridyne 13, which is in agreement with the
bromopyridyne 13 yielded exclusively the isomer indicative of an and cycloaddition reactions (Table 2). In comparison with unsubsti-
initial C3 addition (entry 6, Table 1). When N-t-butyl-a- tuted pyridyne 2, sulfamate 16 was found to react with enhanced
phenylnitrone (entry 8, Table 1)43,44 and 2-methoxyfuran (entry 10, regioselectivity for addition to C4. For example, in the absence
Table 1 | Regioselectivity studies of pyridynes 2 and 13.
Table 2 | Regioselectivity studies of pyridynes 2 and 16.
TMS
TMS
4
4
R
3
R
3
X
X
X
OTf
CsF
OTf
X
CsF
Trapping
agent
Trapping
agent
N
X
N
N
N
X
N
N
2 X = H
2 X = H
16 X = OSO2NMe2
20 X = H
22 X = Br
20 X = H
25 X = OSO2NMe2
13 X = Br
Entry Trapping
agent
Products
Ratio
(yield)*
Entry Trapping
Products
Ratio
(yield)*
agent
Me
N
Me
1
X ¼ H
1.9:1
(77%)
X ¼ Br
1:5.8
1
X ¼ H
1.9:1
(77%)
3
3
X
N
Me
N
Me
N
4
Me
N
Me
N
N
H
H
4
X
þ
þ
þ
N
X
N
2
2
X ¼ OSO2NMe2
N
X
.15:1
(64%)
(64%)
O
O
O
O
N
O
O
3
X ¼ H
3
X ¼ H
1.3:1
(73%)
X ¼ Br
1:2.9
3
N
X
X
3
N
1.3:1
N
H
N
4
N
H
(73%)
X ¼ OSO2NMe2
12:1
4
þ
þ
X
N
N
4
4
N
X
N
N
(64%)
(64%)
O
Me
O
Me
Me
N
Me
N
Me
Me
N
5
6
X ¼ H
5
X ¼ H
2.1:1
N
N
4
4
Me
N
Me
Me
Me
N
O
O
X
N
2.1:1
N
þ
þ
þ
(68%)†
X ¼ OSO2NMe2
C4 only
(79%)
O
O
X
(68%)†
X ¼ Br
C3 only
(72%)
N
N
X
N
X
3
N
Me
3
Me
6
N
N
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
Ph
7
8
X ¼ H
7
8
X ¼ H
1.9:1
(76%)
X ¼ Br
1:3.3
+
+
N
N
O
N
N
N
N
O
1.9:1
þ
þ
4
4
– O
Ph
O
Ph
O
O
X
X
Ph
Ph
(76%)
3
3
X ¼ OSO2NMe2
N
X
N
X
N
N
10.7:1
(61%)
(60%)
O
MeO
X
O
MeO
OMe
OMe
9
X ¼ H
1.3:1
9
X ¼ H
O
O
4
4
O
O
X
1.3:1
OMe
OMe
(64%)‡
X ¼ Br
1:1.7
(64%)‡
X ¼ OSO2NMe2
1.8:1
3
3
N
N
X
N
N
X
10
10
(68%)†
(60%)†
Reactions of silyltriflates 20 and 22 with CsFand trapping agents are shown (see the Supplementary
Reactions of silyltriflates 20 and 25 with CsFand trapping agents are shown (see the Supplementary
Information for details). *Yields refer to isolated yields unless otherwise stated, and ratios refer to
relative amounts of C4 to C3 adducts. †Yield determined by 1H NMR spectroscopy using an
external standard. ‡This Diels–Alder cycloadduct readily underwent isomerization to the
corresponding isoquinoline; the yield refers to the isolated yield of the isoquinoline (see the
Supplementary Information for details).
Information for details). *Yields refer to isolated yields unless otherwise stated, and ratios refer to
†
relative amounts of C4 to C3 adducts. Yield determined by 1H NMR spectroscopy using an
external standard. ‡This Diels–Alder cycloadduct readily underwent isomerization to give the
corresponding isoquinoline; the yield refers to the isolated yield of the isoquinoline (see the
Supplementary Information for details).
4
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1504
ARTICLES
a
b
Disfavoured electronically,
Favoured electronically,
disfavoured sterically
favoured sterically
‡
‡
t-Bu
N
O
t-Bu
Ph
Ph
2-Sulfamoyl-
3,4-pyridyne
5-Bromo-
3,4-pyridyne
N
t-Bu
t-Bu
+
N
+
N
Ph
4
Ph
O
Br
O
4
O –
Br
3
3
2
5
N
N
OR
t-Bu
+N
–O
t-Bu
+ N
–O
Minor product
observed experimentally
Major product
observed experimentally
N
N
OR
δ–
TS3
δ+
TS1
Ph
Ph
δ+
δ–
Br
versus
versus
5
2
N
N
OR
‡
‡
t-Bu
t-Bu
t-Bu
N+
t-Bu
N+
N
O
N
O
16
13
–O
4
– O
4
Br
Ph
Ph
Ph
Ph
Br
3
3
5
N
OR
N
2
N
OR
N
Major product
observed experimentally
Minor product
observed experimentally
TS4
TS2
Favoured electronically,
disfavoured sterically
Disfavoured electronically,
favoured sterically
Figure 4 | Competition between steric interactions and electronic effects in transition states for nitrone cycloadditions. a, TS1 shows the steric interaction
between the C5 bromide and the large phenyl group of the nitrone, whereas this interaction is not present in TS2. However, the major product suggests that
TS1 is favoured because of electronic effects. b, TS4 shows the steric interaction between the C2 sulfamate and the phenyl group on the nitrone, but the
product arising from this transition state is favoured over the competing sterically favourable pathway, TS3.
of the C2 sulfamate, addition of N-methylaniline gave a 1.9:1 arynes26. We surmise that this notion also holds for substituted
mixture of C4:C3 adducts (entry 1, Table 2), whereas the presence 3,4-pyridynes and that 5-bromo and 2-sulfamoyl substituents
of the sulfamate led to an overwhelming preference for attack at induce aryne distortion to favour attack by nucleophiles at C3 and
C4 (entry 2, Table 2). Similar results were obtained for the addition C4, respectively. The origin of distortion and regioselectivity is
of morpholine (entries 3 and 4, Table 2). When DMI was employed believed to stem from an inductive effect imparted by the
to trap sulfamate 16, we obtained a single isomer in 79% yield, sug- electron-withdrawing substituents that can polarize the aryne
gestive of an initial attack at C4 (entry 6, Table 2). For comparison, triple bond in the manners suggested in Fig. 4.
only a 2.1:1 ratio of products was observed using pyridyne 2 (entry
Although steric factors may contribute to the regioselectivities
5, Table 2). N-t-butyl-a-phenylnitrone also displayed excellent observed in nucleophilic additions to substituted 3,4-pyridynes,
selectivity for an initial attack at C4 (entry 8, Table 2), despite the experimental results emphasize the importance of electronic con-
steric burden encountered in the assumed transition state. Finally, siderations. Figure 4 shows the probable transition structures for
the use of 2-methoxyfuran to trap sulfamoylpyridyne 16 led to a the reactions between N-t-butyl-a-phenylnitrone and pyridynes
modest improvement in the preference for an initial attack at C4 13 and 16, respectively. In each case the major product arises
(entry 10, Table 2) compared with that for the parent pyridyne 2 from the electronically matched transition structures (that is, TS1
(entry 9, Table 2).
and TS4), despite these being more sterically encumbered than
TS2 and TS3, respectively. Thus, although steric considerations
Explanation for the observed regioselectivities in reactions of should be considered and may impact ratios of products, the elec-
substituted pyridynes. Previously, it was suggested that aryne tronic nature of these substituents appears to be the guiding factor
distortion governs regioselectivity in reactions of unsymmetrical in reactions of substituted 3,4-pyridynes.
a
Me
b
N
Me
O
N
Me
N
O
NH
MeO
B(OH)2
O
NH
MeO
MgBr
NiClCpIMes,
Br
N
O
Me
Pd(OAc)2, rac-BINAP,
NaO-t-Bu, PhMe, 80 ºC
Pd(PPh3)4, Na2CO3,
EtOH, PhMe, H2O, 75 ºC
(87% yield)
Ni(cod)2, SIPr·HCl
NaO-t-Bu,
1,4-dioxane, 80 ºC
THF, 40 ºC
N
OSO2NMe2
30
N
(82% yield)
(67% yield)
26
(58% yield)
H2, Pd/C,
EtOAc, NEt3
(88% yield)
Ni(cod)2, SIPr·HCl,
TMDSO, K3PO4, NaO-t-Bu,
p-xylene, 130 ºC
(49% yield)
Me
Me
Me
Me
N
Me
Me
N
Me
O
N
N
N
O
N
N
MeO
O
Me
O
O
N
Me
N
O
O
N
H
N
N
N
N
O
Me
Me
Me
N
N
N
H
N
N
N
OMe
28
32
27
29
31
33
Pd-catalysed
amination
Pd-catalysed
reduction
Pd-catalysed
arylation
Ni-catalysed
amination
Ni-catalysed
reduction
Ni-catalysed
arylation
Figure 5 | Derivatization of adducts 26 and 30. a, Pd-catalysed amination, reduction and Suzuki coupling of pyridyl bromide 26. b, Ni-catalysed amination,
reduction and Kumada coupling of pyridyl sulfamate 30. BINAP ¼ 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, Ni(cod)2 ¼ bis(cyclooctadiene)nickel(0),
′
5
.
SIPrHCl ¼ N,N -(2,6-diisopropylphenyl)dihydroimidazolium chloride, TMDSO ¼ tetramethyldisiloxane, NiClCpIMes ¼ (h -C5H5)NiCl(1,3-dimesitylimidazol-
2-ylidene).
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.
5

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1504
ARTICLES
10. Gribble, G. W., Saulnier, M. G., Sibi, M. P. & Obaza-Nutaitis, J. A. Synthesis and
Diels–Alder reactions of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole.
A new annulation strategy for the construction of ellipticine and isoellipticine.
J. Org. Chem. 49, 4518–4523 (1984).
11. May, C. & Moody, C. J. A new precursor to 3,4-didehydropyridine, and its use in
the synthesis of the antitumor alkaloid ellipticine. J. Chem. Soc. Perkin Trans. 1
247–250 (1988).
Derivatization of pyridyne adducts using Pd or Ni catalysis. As
shown in Fig. 5, the halide and sulfamoyl substituents can be
removed or used as functional group handles for further
elaboration. Bromide 26 and sulfamate 30, each of which was
accessed as a single regioisomer from its corresponding pyridyne
precursor (see entry 6, Table 1 and entry 6, Table 2, respectively),
were selected as the substrates for these studies. Structures 26 and
30 are reminiscent of the medicinally important benzodiazepines45
and, therefore, serve as an ideal testing ground for bromide- and
sulfamate-based derivatizations of pyridyne adducts.
´
´
12. Dıaz, M. T., Cobas, A., Guitian, E. & Castedo, L. Polar control of the regioselectivity
of hetaryne cycloadditions. Synthesis of ellipticine. Synlett 157–158 (1998).
´
´
13. Dıaz, M. T., Cobas, A., Guitian, E. & Castedo, L. Synthesis of ellipticine by
hetaryne cycloadditions – control of regioselectivity. Eur. J. Org. Chem.
4543–4549 (2001).
14. Enamorado, M. F., Ondachi, P. W. & Comins, D. L. A five-step synthesis of (S)-
macrostomine from (S)-nicotine. Org. Lett. 12, 4513–4515 (2010).
15. Nam, H-H. & Leroi, G. E. First direct observation of pyridyne: matrix infrared
study of the photolysis products of 3,4-pyridinedicarboxylic anhydride. J. Am.
Chem. Soc. 110, 4096–4097 (1988).
Bromide 26 underwent a smooth reaction using Pd catalysis to
afford various analogues (Fig. 5). Buchwald–Hartwig amination
gave the amine derivative 27 in 67% yield, whereas Suzuki–
Miyaura coupling furnished the arylated product 29 in 87% yield.
Additionally, it was found that the bromide could be removed
under Pd-catalysed hydrogenolysis conditions to deliver 28 in
high yield.
Also, we were delighted to find that sulfamate 30 could be func-
tionalized readily using Ni catalysis (Fig. 5). Sulfamate amination
provided aminopyridine 31 in 58% yield46. Furthermore, a Ni-cata-
lysed Kumada–Corriu coupling47 proceeded smoothly using the
readily prepared, and bench-stable, (h5-C5H5)NiCl(1,3-dimesityl-
imidazol-2-ylidene) complex to give biaryl 33 in 82% yield.
Finally, we found that the sulfamate could be removed under
reductive conditions48,49 to afford 32, which marks the first
example of reductive sulfamate cleavage. The straightforward
manipulations of 26 and 30 demonstrate that (1) using this
methodology diverse arrays of highly substituted pyridine
derivatives are accessible in a highly controlled fashion, and (2)
the aryl sulfamate group may be manipulated readily through
modern Ni-catalysed coupling reactions, even when adorned with
a complex heterocyclic system.
In summary, we have developed the first general method to
govern 3,4-pyridyne regioselectivities. Our approach relies on the
strategic use of bromide- and sulfamate-directing groups that can
be removed or exploited as synthetic handles for further elaboration
using transition-metal catalysis. Using this methodology, unique di-
and trisubstituted pyridine derivatives can be accessed with a signifi-
cant control of regiochemistry. These studies further validate the
aryne distortion model and its predictive capabilities in gauging
aryne regioselectivities. We expect our findings will promote the
use of 3,4-pyridynes and other heterocyclic arynes in the synthesis
of medicinally privileged molecular scaffolds.
´
`
16. Jamart-Gregoire, B., Leger, C. & Caubere, P. New applications of complex
bases: nucleophilic condensations of pyridyne. Tetrahedron Lett. 131,
7599–7602 (1990).
17. Sha, C-K. & Yang, J-F. Total syntheses of ellipticine alkaloids and their amino
analogues. Tetrahedron 48, 10645–10654 (1992).
18. Tsukazaki, M. & Snieckus, V. Synthetic connections to the directed ortho
metalation reaction. 3,4-Pyridynes from 4-trialkylsilyl-3-pyridyl triflates.
Heterocycles 33, 533–536 (1992).
´
`
19. Vinter-Pasquier, K., Jamart-Gregoire, B. & Caubere, P. Complex base-induced
generation of 3,4-didehydropyridine derivatives: new access to aminopyridines
or pyridones. Heterocycles 45, 2113–2129 (1997).
20. Walters, M. A. & Shay, J. J. 2,3-Pyridyne formation by fluoride-induced
desilylation-elimination. Synth. Commun. 27, 3573–3579 (1997).
21. Carroll, F. I. et al. Synthesis and nicotinic acetylcholine receptor binding
properties of bridged and fused ring analogues of epibatidine. J. Med. Chem. 50,
6383–6391 (2007).
22. Lin, W., Chen, L. & Knochel, P. Preparation of functionalized 3,4-pyridynes via
2-magnesiated diaryl sulfonates. Tetrahedron 63, 2787–2797 (2007).
23. Jiang, L., Yu, X., Fang, B. & Wu, J. Silver triflate-catalyzed tandem reaction of
N′-(2-alkynylbenzylidene)hydrazide with pyridyne. Org. Biomol. Chem. 10,
8102–8107 (2012).
24. Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural
product total synthesis. Chem. Rev. 112, 3550–3577 (2012).
25. Reinecke, M. G. Hetarynes. Tetrahedron 38, 427–498 (1982).
26. Cheong, P. H-Y. et al. Indolyne and aryne distortions and nucleophilic
regioselectivities. J. Am. Chem. Soc. 132, 1267–1269 (2010).
27. Im, G-Y. J. et al. Indolyne experimental and computational studies: synthetic
applications and origins of selectivities of nucleophilic additions. J. Am. Chem.
Soc. 132, 17933–17944 (2010).
28. Goetz, A. E. et al. An efficient computational model to predict the synthetic
utility of heterocyclic arynes. Angew. Chem. Int. Ed. 51, 2758–2762 (2012).
29. Spartan 06 (Wavefunction Inc., Irvine, California, 2006).
30. Bronner, S. M., Goetz, A. E. & Garg, N. K. Overturning indolyne regioselectivities
and synthesis of indolactam V. J. Am. Chem. Soc. 133, 3832–3835 (2011).
31. Rau, N. J. & Wenthold, P. G. Experimental investigation of the absolute
enthalpies of formation of 2,3-, 2,4-, and 3,4-pyridynes. J. Phys. Chem. A 115,
10353–10362 (2011).
Received 9 May 2012; accepted 18 October 2012;
published online 25 November 2012
32. Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of
o-trimethylsilylphenyl triflate to benzyne under mild conditions Chem. Lett. 12,
1211–1214 (1983).
References
33. Rosen, B. M. et al. Nickel-catalyzed cross-couplings involving carbon–oxygen
1. Pozharskii, A. F., Soldatenkov, A. & Katritzky, A. R. Heterocycles in Life and
Society: An Introduction to Heterocyclic Chemistry, Biochemistry, and
Applications 2nd edn (Wiley, 2011).
bonds. Chem. Rev. 111, 1346–1416 (2011).
´
´
34. Quintana, I., Boersma, A. J., Pen˜a, D., Perez, D., & Guitian, E. Metal-catalyzed
cotrimerization of arynes and alkenes. Org. Lett. 8, 3347–3349 (2006).
35. Gerfaud, T., Neuville, L. & Zhu, J. Palladium-catalyzed annulation of acyloximes
with arynes (or alkynes): synthesis of phenanthridines and isoquinolines. Angew.
Chem. Int. Ed. 48, 572–577 (2009).
2. Joule, J. A. & Mills, K. Heterocyclic Chemistry 5th edn (Wiley, 2010).
3. Colby, D. A., Bergman, R. G. & Ellman, J. A. Synthesis of dihydropyridines and
pyridines from imines and alkynes via C–H activation. J. Am. Chem. Soc. 130,
3645–3651 (2008).
36. Yoshida, H., Shirakawa, E., Honda, Y. & Hiyama, T. Addition of ureas to arynes:
straightforward synthesis of benzodiazepine and benzodiazocine derivatives.
Angew. Chem. Int. Ed. 41, 3247–3249 (2002).
4. Fischer, D. F. & Sarpong, R. Total synthesis of (þ)-complanadine A using an
iridium-catalyzed pyridine C–H functionalization. J. Am. Chem. Soc. 132,
5926–5927 (2010).
37. Yoshida, H., Fukushima, H., Ohshita, J. & Kunai, A. Arynes in a three-
component coupling reaction: straightforward synthesis of benzoannulated
iminofurans. Angew. Chem. Int. Ed. 43, 3935–3938 (2004).
38. Toledo, F. T., Comasseto, J. V. & Raminelli, C. Selenostannylation of arynes
produced by silylaryl triflates under mild reaction conditions. J. Braz. Chem.
Soc. 21, 2164–2168 (2010).
5. Seiple, I. B. et al. Direct C–H arylation of electron-deficient heterocycles with
arylboronic acids. J. Am. Chem. Soc. 132, 13194–13196 (2010).
6. Ye, M. et al. Ligand-promoted C3-selective arylation of pyridines with Pd
catalysts: gram-scale synthesis of (+)-preclamol. J. Am. Chem. Soc. 133,
19090–19093 (2011).
7. Levine, R. & Leake, W. W. Rearrangement in the reaction of
3-bromopyridine with sodium amide and sodioacetophenone. Science 121,
780 (1955).
39. Effenberger, F. & Daub, W. Darstellung von didehydropyridinen aus
(trimethylsilyl)pyridinen. Chem. Ber. 124, 2119–2125 (1991).
40. Vorbru¨ggen, H. & Krolikiewicz, K. Silylation-amination of hydroxy
8. Zoltewicz, J. A. & Nisi, C. Trapping of 3,4-pyridyne by thiomethoxide ion in
ammonia. J. Org. Chem. 34, 765–766 (1969).
N-heterocycles. Chem.
Ber. 117, 1523–1541 (1984).
9. May, C. & Moody, C. J. A concise synthesis of the antitumor alkaloid ellipticine.
J. Chem. Soc. Chem. Commun. 926–927 (1984).
41. Kaye, H. & Chang, S-H. N-Vinylation of heteroaromatic O-trimethylsilyl
lactims. Tetrahedron 26, 1369–1376 (1970).
6
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1504
ARTICLES
42. Liu, Z. & Larock, R. C. Facile N-arylation of amines and sulfonamides and
O-arylation of phenols and arenecarboxylic acids. J. Org. Chem. 71,
3198–3209 (2006).
43. Matsumoto, T., Sohma, T., Hatazaki, S. & Suzuki, K. On the regiochemistry
of cycloaddition of unsymmetrical aryne with nitrone. Remarkable effect of
trialkylsilyl substituent. Synlett 843–846 (1993).
44. Dai, M., Wang, Z. & Danishefsky, S. J. A novel a,b-unsaturated nitrone-aryne
[3þ2] cycloaddition and its application in the synthesis of the cortistatin core.
Tetrahedron Lett. 49, 6613–6616 (2008).
Acknowledgements
The authors are grateful to Boehringer Ingelheim, DuPont, Eli Lilly, Amgen, AstraZeneca,
Roche, the A. P. Sloan Foundation, the University of California, Los Angeles, the ACS
Division of Organic Chemistry (fellowship to A.E.G.) and the Foote Family (fellowship to
A.E.G.) for financial support. Jordan Cisneros (University of California, Los Angeles) is
acknowledged for experimental assistance and thanks Pfizer for financial support. These
studies were supported by shared instrumentation grants from the National Science
Foundation (CHE-1048804) and the National Center for Research Resources
(S10RR025631).
45. Hadjipavlou–Litina, D. & Hansch, C. Quantitative structure–activity
relationships of the benzodiazepines. A review and reevaluation. Chem. Rev.
94, 1483–1505 (1994).
46. Ramgren, S. D., Silberstein, A. L., Yang, Y. & Garg, N. K. Nickel-catalyzed
amination of aryl sulfamates. Angew. Chem. Int. Ed. 50, 2171–2173 (2011).
47. Macklin, T. K. & Snieckus, V. Directed ortho-metalation methodology. The N,N-
dialkyl aryl O-sulfamate as a new directed metalation group and cross-coupling
partner for Grignard reagents. Org. Lett. 7, 2519–2522 (2005).
48. Sergeev, A. G. & Hartwig, J. F. Selective, nickel-catalyzed hydrogenolysis of aryl
ethers. Science 332, 439–443 (2011).
Author contributions
A.E.G. planned and carried out the experimental work. A.E.G. and N.K.G. conceived the
project, co-wrote the manuscript and commented on the manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permission information is available online at
http://www.nature.com/reprints. Correspondence and requests for materials should be
addressed to N.K.G.
49. Mesganaw, T., Fine Nathel, N. F. & Garg, N. K. Cine substitution of arenes
using the aryl carbamate as a removable directing group. Org. Lett. 14,
2918–2921 (2012).
Competing financial interests
The authors declare no competing financial interests.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
7
© 2012 Macmillan Publishers Limited. All rights reserved.