Generation and regioselective trapping of a 3,4-piperidyne for the synthesis of functionalized heterocycles

Article abstract of DOI:10.1021/jacs.5b01589

We report the generation of the first 3,4-piperidyne and its use as a building block for the synthesis of annulated piperidines. Experimental and computational studies of this intermediate are disclosed, along with comparisons to the well-known 3,4-pyridyne. The distortion/interaction model is used to explain the observed regioselectivities.

Full text of DOI:10.1021/jacs.5b01589

Communication
pubs.acs.org/JACS
Generation and Regioselective Trapping of a 3,4-Piperidyne for the
Synthesis of Functionalized Heterocycles
†
†
Travis C. McMahon, Jose M. Medina, Yun-Fang Yang, Bryan J. Simmons, K. N. Houk,*
and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
*
S Supporting Information
used as a new synthetic building block. Notably, 3,4-piperidynes
have never been accessed previously. The most closely related
studies have involved the isomeric 2,3-piperidyne 2, which has
been the subject of two seminal investigations. In 1988, Wentrup
and co-workers generated 2 (R = H) using flash vacuum
ABSTRACT: We report the generation of the first 3,4-
piperidyne and its use as a building block for the synthesis
of annulated piperidines. Experimental and computational
studies of this intermediate are disclosed, along with
comparisons to the well-known 3,4-pyridyne. The
distortion/interaction model is used to explain the
observed regioselectivities.
2
pyrolysis. Although 2 was deemed unstable above −150 °C and
was never utilized in any synthetic application, Wentrup’s studies
validated the notion that 2 could be generated. Additionally,
during the preparation of this communication, Danheiser
disclosed an efficient means to access 2 (R = Ts) and performed
3
eterocycles containing one or more nitrogen atoms
a series of synthetically useful trapping reactions. Interestingly,
4
H
constitute nearly 60% of all small-molecule drugs tha1t
have been approved by the U.S. Food and Drug Administration.
The most prevalent N-containing heterocycle is the piperidine
ring, which is found in 72 currently marketed small-molecule
drugs. Notable examples include the blockbuster drugs
clopidogrel (Plavix), tadalafil (Cialis), and solifenacin (VES-
Icare) (Figure 1). In view of the importance of this medicinally
privileged scaffold, new methods to rapidly access annulated
piperidines from simple precursors are highly sought after.
With the aim of developing a new method for the synthesis of
decorated piperidines, we questioned whether the unusual 3,4-
piperidyne intermediate 1 (Figure 1) could be generated and
whereas piperidynes have been rarely studied, the correspond-
5
6
ing aromatic pyridynes 3 and 4, along with many other arynes
and hetarynes, have been widely pursued for more than half a
7
−9
century.
Herein we report: (a) the first generation of a 3,4-piperidyne 1;
(
b) the strategic use of 1 to construct a range of functionalized
piperidines, many of which possess significant aliphatic
1
0
character and represent new heterocyclic scaffolds; (c)
regioselectivity predictions, observations, and explanations
involving the 3,4-piperidyne, which are in accord with the
7a,e,8g
distortion/interaction model;
and (d) an explanation for
the lack of selectivity observed in trapping experiments of the 3,4-
pyridyne (3), which has been unresolved for many decades.
We initiated our studies by applying the distortion/interaction
11
model to our targeted piperidyne, Cbz-derivative 1a, in order
to assess the likelihood that it would undergo regioselective
trapping in reactions with nucleophiles and cycloaddition
partners (Figure 2). In previous studies, we showed that the
degree of distortion present in the ground state of arynes and
Figure 2. Optimized structures of 1a and 3 obtained at the B3LYP/6-
3
1G(d) level.
Figure 1. Piperidine-containing blockbuster drugs, piperidynes 1 and 2,
and pyridynes 3 and 4.
Received: February 12, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b01589
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Journal of the American Chemical Society
Communication
strained alkynes is correlated with the observed regioselectivity
because the intermediate is predistorted toward one of two
Table 1. Diels−Alder Cycloadditions of 3,4-Piperidyne 1a
7
a,e,8g,9
competing transition states.
Geometry optimization using
DFT calculations (B3LYP/6-31G(d)) revealed that 1a is
significantly distorted (ca. 10° difference in internal angles at
C4 and C3), such that nucleophilic addition should occur
preferentially at the more linear terminus (C4). As a key point of
comparison, we also studied 3,4-pyridyne 3, which is well-known
7
a,e,8g,12
to react with poor regioselectivity,
as mentioned earlier.
In contrast to 1a, the geometry-optimized structure of 3 shows
little unsymmetrical distortion. Given this interesting dichotomy,
we envisioned that experimental studies of 3,4-piperidyne 1a
would not only test our regioselectivity predictions but also could
ultimately shed light on why 3,4-pyridyne 3 is not significantly
distorted and, accordingly, reacts with poor regioselectivity.
The success of our study would rely on the development of an
efficient synthesis of a suitable 3,4-piperidyne precursor. After
1
1,13
identifying silyl triflate 8 as our target,
we developed the
robust and scalable three-step route shown in Scheme 1.
a
Reported yields are averages of two experiments and are based on the
Scheme 1. Synthesis of Silyl Triflate 8
amounts of isolated products.
Table 2. Reactions of Silyl Triflate 8 with Nucleophiles and
Cycloaddition Partners
Beginning from commercially available 4-methoxypyridine (5), a
known procedure was employed to effect ortho silylation to yield
1
4
silylpyridine 6. Next, a one-pot procedure involving reductive
15
carbamoylation and hydrolysis provided vinylogous amide 7 in
excellent yield. Finally, conjugate reduction followed by trapping
16
of the resultant enolate with Tf O provided silyl triflate 8. The
2
sequence was performed on a gram scale and provided 8 in 51%
1
7
overall yield from 5.
To validate that the 3,4-piperidyne could be generated, we
performed a series of Diels−Alder trapping experiments to
produce a variety of annulated products (Table 1). Specifically,
silyl triflate 8 was treated with CsF in the presence of several
trapping agents (3 equiv) in acetonitrile at 60 °C. The use of
tetracyclone as the trapping agent delivered a tetrahydroisoqui-
noline product in 76% yield via cycloaddition followed by loss of
CO (entry 1). An alternate tetrahydroisoquinoline was accessed
upon trapping of the intermediate 3,4-piperidyne with 2-pyrone
by way of a Diels−Alder/retro-Diels−Alder sequence with
concomitant loss of CO (entry 2). Additionally, cycloadditions
2
with 2,5-dimethylfuran and N-Boc-pyrrole provided the
corresponding piperidine-fused [2.2.1]-bridged bicyclic products
(
entries 3 and 4).
Encouraged by our initial success, we carried out trapping
experiments of 3,4-piperidyne 1a with a variety of nucleophiles
and unsymmetrical cycloaddition partners (Table 2). In addition
to acting as a probe for our regioselectivity predictions, some of
the transformations provide access to interesting heterocyclic
products. Nucleophilic addition experiments were performed
with imidazole and morpholine (entries 1 and 2). In both cases,
addition occurred exclusively at C4, consistent with our earlier
prediction and differing from the known trends of 3,4-pyridyne
reactions. An analogous regiochemical preference was observed
in a series of cycloaddition reactions. For example, trapping with
a
Reported yields are averages of two experiments and are based on the
b
amounts of isolated products. The yield was determined using 1,3,5-
trimethoxybenzene as an external standard.
a nitrone afforded isoxazoline products in good yield with a
significant regiochemical preference of 12.7 to 1 (entry 3). In (3
+ 2) cycloadditions using azide and diazo coupling partners,
triazole and pyrazole products, respectively, were obtained
B
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Journal of the American Chemical Society
entries 4 and 5). Pyridine- and N-phenylpyrazole-containing
Communication
(
versus C3 (TS1 and TS2, respectively) is negligible. This is
24,25
annulated products could be obtained as well, albeit with lower
consistent with the low regioselectivity seen experimentally.
18
selectivities (entries 6 and 7).
As these are very early transition states, the distortion energy
(ΔE ), i.e., the energy required to alter the alkyne geometry
toward the transition state, is expected to be small; in fact, we do
dist
Several salient features regarding this methodology and the
products shown in Tables 1 and 2 should be noted. (a)
Analogous to known reactions of arynes using silyl triflate
precursors, 3,4-piperidyne trapping experiments are operation-
ally trivial to perform and generally do not require the rigorous
exclusion of oxygen or moisture. (b) Silyl triflate 8, which is now
being commercialized to enable its widespread use in drug
dist
calculate a slightly greater ΔE of the alkyne for TS2 than TS1
(ca. 0.2 kcal/mol). In contrast, the addition of morpholine to C4
of 3,4-piperidyne 1a (TS3) is predicted to be favored over attack
at C3 (TS4) by roughly 1.7 kcal/mol. Notably, the disparity in
dist
ΔE accounts for most of the energetic difference and the
1
7
discovery, can be used as a single precursor in order to access a
variety of annulated piperidines. This stands in contrast to more
conventional strategies, which would involve the development of
an independent synthesis of each annulated piperidine desired.
resulting high regioselectivity observed experimentally (see
Table 2, entry 2). These results validate that the distortion/
interaction model correctly predicts and explains the regiose-
lectivities in reactions of both 3 and 1a.
(
c) Several of the products accessed by our methodology
As noted earlier, the lack of regioselectivity seen in reactions of
3,4-pyridynes has been a long-standing problem. Thus, we
sought to probe one remaining critical question: why is the 3,4-
piperidyne significantly distorted while the 3,4-pyridyne is not?
The explanation is summarized in Figure 4. The distortion of 3,4-
represent new scaffolds, including the unique compounds shown
19
in entries 3 and 4 in Table 1 and entries 3 and 6 in Table 2. (d)
Many of the cycloaddition adducts shown in Table 2 are new
analogues of known medicinally important scaffolds. For
example, compounds related to those in entries 4, 5, and 7
20
21
show promise for the treatment of inflammation, diabetes,
2
2
23
cancer, hepatitis C, and other illnesses. (e) Finally, with
regard to regioselectivity, it should be emphasized that 3,4-
piperidyne 1a uniformly reacts with a preference for initial attack
at C4, which is the same trend as seen in reactions of the well-
studied 3,4-pyridyne 3. However, the observed selectivities in the
case of 1a are generally greater than those seen in the trapping of
2
4
3,4-pyridynes.
Figure 4. Explanation of the differing distortion seen in 1a and 3.
To understand the disparity in the regioselectivities of the
reactions of 3 and 1a, we used DFT calculations to analyze the
competing transition states for the nucleophilic addition of
morpholine to 3 and compared the results to the corresponding
transition states involving 1a (Figure 3). In the reactions of 3
with morpholine, the difference in the energies for attack at C4
piperidyne 1a is caused by the electronegativity of the N
heteroatom, which deforms the triple bond as a result of Bent’s
26
rule. The internal bond angle at C3 is decreased, mixing in p
character at C3 and releasing electron density toward the
electronegative N atom. Although the analogous effect is also
present in 3,4-pyridyne 3, it is offset by the in-plane overlap of the
nitrogen lone pair with the π and π* orbitals at C3, which causes
C3 to move toward the N atom (for further discussion of these
competing effects, see the Supporting Information). Such an
effect is not seen in 1a, as the nitrogen lone pair is orthogonal to
the π and π* orbitals of the alkyne.
In summary, we have synthesized the first 3,4-piperidyne, 1a,
and demonstrated that this reactive intermediate can be utilized
in a variety of cycloadditions to form annulated piperidine
scaffolds. The regioselectivity trends observed in reactions of 1a
with nucleophiles and unsymmetrical cycloaddition partners are
predicted and rationalized by the distortion/interaction model.
Moreover, we have explained the inductive effect that causes the
distortion seen in 1a in addition to the competing inductive
effects and orbital interactions that result in the lack of
regioselectivity observed in reactions of the well-studied 3,4-
pyridyne (3). Our findings not only provide a new platform to
access medicinally privileged piperidine scaffolds, but also lay the
foundation for further studies geared toward strategically
harnessing strained heterocyclic alkynes as useful synthetic
building blocks.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental and compound characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
*
S
Figure 3. Optimized transition states for nucleophilic addition of
morpholine to 3 and 1a at the B3LYP/6-31G(d) level. Single-point
energies were calculated at the B3LYP-D3/6-311+G(d,p) level with the
−1
CPCM solvent model for MeCN. Energies are provided in kcal mol .
C
DOI: 10.1021/jacs.5b01589
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(
12) For recent examples of 3,4-pyridyne regioselectivities, see:
AUTHOR INFORMATION
Corresponding Authors
houk@chem.ucla.edu
neilgarg@chem.ucla.edu
■
(
a) Enamorado, M. F.; Ondachi, P. W.; Comins, D. L. Org. Lett. 2010,
1
2, 4513. (b) Saito, N.; Nakamura, K.-i.; Shibano, S.; Ide, S.; Minami, M.;
*
Sato, Y. Org. Lett. 2013, 15, 386. (c) Saito, N.; Nakamura, K.-i.; Sato, Y.
Heterocycles 2014, 88, 929.
*
Author Contributions
T.C.M. and J.M.M. contributed equally.
Notes
(13) Given the widespread use of silyl triflates in aryne and cycloalkyne
trapping experiments (using mild fluoride-based conditions), we
deemed silyl triflate to be 8 an ideal target.
†
(
14) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
994, 116, 4719.
15) Knapp, S.; Yang, C.; Pabbaraja, S.; Rempel, B.; Reid, S.; Withers, S.
G. J. Org. Chem. 2005, 70, 7715.
The authors declare no competing financial interest.
1
(
ACKNOWLEDGMENTS
■
The authors are grateful to the NIH NIGMS (R01 GM090007 to
N.K.G.), the National Science Foundation (CHE-1361104 to
K.N.H.), Bristol-Myers Squibb, DuPont, the Alfred P. Sloan
Foundation, the S. T. Li Foundation, the Dreyfus Foundation,
the UC Cancer Research Coordinating Committee, and the
UCLA Cota Robles Fellowship Program (J.M.M.) for financial
support. This work used the Extreme Science and Engineering
Discovery Environment (XSEDE), which is supported by the
National Science Foundation (OCI-1053575) along with the
UCLA Institute of Digital Research and Education (IDRE).
These studies were supported by shared instrumentation grants
from the NSF (CHE-1048804) and the National Center for
Research Resources (S10RR025631).
́ ́
(16) Atanes, N.; Escudero, S.; Perez, D.; Guitian, E.; Castedo, L.
Tetrahedron Lett. 1998, 39, 3039.
(
17) Aldrich Chemical Co, Inc. is currently commercializing silyl
triflate 8, which will be available by mid 2015.
18) For entry 6, substantial mass was lost to nonproductive reaction
(
pathways, which may render the regioselectivity data unreliable. In the
case of entry 7, the lack of regioselectivity can be attributed to the
sydnone trappings occurring through concerted, highly synchronous
transition states with low activation barriers. Larock and Shi have
reported similarly modest regioselectivities using 3-methoxybenzyne
with the sydnone trapping agent. See: Fang, Y.; Wu, C.; Larock, R. C.;
Shi, F. J. Org. Chem. 2011, 76, 8840.
(19) Structural similarity searches were performed using SciFinder
Scholar. Other scaffolds, including the minor adduct from the diazo ester
cycloaddition (Table 2, entry 5) and the major product from the
sydnone cycloaddition (Table 2, entry 7) are also difficult to access.
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(
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(
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D
DOI: 10.1021/jacs.5b01589
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX