Trimethylsilyl-Protected Alkynes as Selective Cross-Coupling Partners in Titanium-Catalyzed [2+2+1] Pyrrole Synthesis

Article abstract of DOI:10.1002/anie.201800595

Trimethylsilyl (TMS)-protected alkynes served as selective alkyne cross-coupling partners in titanium-catalyzed [2+2+1] pyrrole synthesis. Reactions of TMS-protected alkynes with internal alkynes and azobenzene under the catalysis of titanium imido comple

Full text of DOI:10.1002/anie.201800595

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Accepted Article
Title: Trimethylsilyl-Protected Alkynes as Selective Cross Coupling
Partners in Ti-Catalyzed [2+2+1] Pyrrole Synthesis
Authors: Hsin-Chun Chiu and Ian A. Tonks
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800595
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10.1002/anie.201800595
Angewandte Chemie International Edition
COMMUNICATION
Trimethylsilyl-Protected Alkynes as Selective Cross Coupling
Partners in Ti-Catalyzed [2+2+1] Pyrrole Synthesis
Hsin-Chun Chiu and Ian A. Tonks*[a]
Previous work:
Abstract: Trimethylsilyl (TMS)-protected alkynes serve as selective
statistical mixtures of homocoupled alkyne pyrroles
alkyne cross coupling partners in Ti-catalyzed [2+2+1] pyrrole
Ph
N
Ph
N
Ph
N
R1
synthesis. Reactions of TMS-protected alkynes with internal alkynes
and azobenzene catalyzed by Ti imido catalysts yield
pentasubstituted 2-TMS-pyrroles with greater than 90% selectivity
over the other 9 possible pyrrole products. The steric and electronic
effects of the TMS group have both been identified to play key roles
in this highly selective pyrrole synthesis. This strategy provides a
convenient methodology to synthesize multisubstituted pyrroles as
well as an entrypoint into further pyrrole diversification through
facile modification of the resulting 2-silylpyrrole products, as
demonstrated through a short formal synthesis of the marine
natural product Lamellarin R.
cat. [Ti]
R1
R1
R2
R2
R1
R2
2
PhN=NPh
[2+2+1]
R2
R2
R2
R1
R2
R1
R1
This work:
regio- and chemo-selective
alkyne heterocoupling
Ph
R2
TMS
cat. [Ti]
N
+
TMS
R2
PhN=NPh
[2+2+1]
R1
R3
R1
R3
Figure 1. General equations of Ti-catalyzed pyrrole formation.
no reaction!
via
Pyrroles are molecules of interest in a variety of fields,
including pharmaceuticals,[1] natural products,[2] dyes[3] and
materials.[4] Even though there are many well-developed methods
for the synthesis of pyrroles, the efficient synthesis of
multisubstituted pyrroles is still challenging. For example the
Paal-Knorr condensation of primary amines with 1,4-diketones
Ph
TMS
+
Ph
5% [py2Cl2TiNPh]2
N
N
LnTi
TMS
PhNH2
X
PhCF3, 115 o
16 h
C
TMS
Ph
Ph
Ph
1a
via
LnTi
Ph
N
0.5 PhNNPh
5% [py2Cl2TiNPh]2
Ph
TMS
+
Me
and
related
cyclization
reactions
require
extensive
N
TMS
Me
2
preconstruction of the carbon backbone and often have limited
PhCF3, 115 o
3 h
C
5]
substitution patterns.[1,
Multicomponent reactions that can
Ph
Ph
Ph
Me
1a
2a
Ph
92% yield
96% selectivity
Ph
circumvent complex precursor synthesis typically require very
specific functional groups or substitution patterns.[6] For example,
many formal [3+2], [2+2+1], and related multicomponent
cycloadditions necessitate electron-withdrawing substituents on
the pyrrole,[6-7] or are limited to the synthesis of mono-, di-, or
trisubstituted pyrrole products.[6a, 8]
Figure 2. Failed [2+2] cycloaddition of 1a (top) led to the exploration of its use
as a partner in selective heterocoupling reactions (bottom).
In the course of our studies, we have found that TMS-
phenylacetylene (1a) is incapable of productive [2+2+1] reactivity.
Attempted hydroamination of 1a with [(py2TiCl2NPh]2 and PhNH2,
which should proceed through [2+2] cycloaddition of the alkyne to
the Ti=NPh imido, resulted in no product formation indicating that
1a is incapable of facile [2+2] addition with simple Ti imido halides
(Figure 2, top). Thus, we hypothesized that they may be suitable
cross-coupling partners with other alkynes that are capable of
[2+2] cycloaddition. To test this hypothesis, we ran the reaction of
1a with 1-phenyl-1-propyne (2a), and found that it gave
remarkably chemo- and regioselective cross coupling of the two
alkyne partners (Figure 2, bottom). This model reaction was
optimized to achieve the highest yield of the crossover pyrrole and
its overall selectivity among all homocoupled and crossover
products (Table S1). Selectivies are fairly good with a 1:1 ratio of
1a:2a, but we chose to use 2 equivalents of 1a in order to simplify
byproduct separation.
Recently, we demonstrated an atom economical method to
synthesize pentasubstituted pyrroles from simple alkynes and
azobenzene via a Ti-catalyzed formal [2+2+1] reaction (Figure 1,
top).[9] However, our initial report was limited to the homocoupling
of alkynes, and unsymmetric alkynes yielded poor, substrate-
controlled regioselectivity. Regioselectivity in other intermolecular
[2+2+1] reactions such as the Pauson-Khand reaction is often
difficult to achieve in the absence of clear stereoelectronic
differentiation of alkyne substituents, and remains a siginficant
synthetic challenge.[10] In an effort to design more useful and
practical pyrrole syntheses, we have explored several routes to
the chemo- and regioselective heterocoupling of alkynes in the
[2+2+1] reaction to yield highly substituted pyrroles. Herein, we
report that silyl-protected alkynes serve as excellent
heterocoupling partners, yielding pentasubstituted N-aryl pyrroles
in high chemo- and regioselectivity (Figure 1, bottom). This
reaction provides a versatile and simple platform for the
construction of highly substituted pyrroles, as well as an
entrypoint into further pyrrole diversification through facile
modification of the resulting 2-silylpyrrole products.
Under the optimized reaction conditions, the substrate
scope was investigated. First, a suite of TMS-protected aryl
alkynes was reacted with 2a (Table 1). All pyrroles were isolated
after hydrolysis of the TMS group, giving 3aa-3ra as the major
regioisomer in almost all cases. Most aryl TMS acetylenes give
exceptionally high yields and selectivies, typically above 90%.
There is no electronic effect on yield or selectivity (3aa-3fa, 3ja-
3la), while sterically encumbered substrates such as 1i are more
difficult to insert, leading to more homocoupling of 2a and slightly
lowered yield/selectivity of the desired 3ia. The reaction shows
reasonably broad functional group tolerance, including aryl
halides (3ca, 3da) and some Lewis basic groups (3ea-3ga; 3la,
3ma’), although aryl nitriles and carbonyl derivatives arrest
catalysis (See SI).
[a]
H.-C. Chiu, Prof. Dr. I. A. Tonks
Department of Chemistry, University of Minnesota – Twin Cities
207 Pleasant St SE, Minneapolis, MN 55455 (USA)
E-mail: itonks@umn.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201800595
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COMMUNICATION
In addition to aryl alkynes, TMS-protected alkyl alkynes
(3na-3pa) all perform well in highly cross selective pyrrole
formation (3na-3op), although sterically encumbered tert-butyl
groups (3qa) do not participate in catalysis and yield only
homocoupled 2a. Notably, conjugated enynes (3pa) are tolerated
in catalysis, providing an additional functional handle on the
resulting pyrrole. TMS2C2 (1r) is also a competent cross coupling
partner, yielding 3aa on workup.
The origins of regio- and chemoselectivity in these
heterocoupling reactions are derived mainly from electronic
factors of both alkyne partners (Figure 3). Regioselectivity in [2+2]
cycloaddition of phenylpropyne derivatives with Ti=NPh is driven
primarily by the electronics of the metallacyclic transition state
(Figure 3, TS1) where the d+ is better stabilized by CH3. This
electronically-driven regioselectivity is also seen in py3TiCl2(NPh)-
catalyzed hydroamination, where N,1-diphenylpropan-2-imine is
the sole product resulting from metallacycle INT1.[13]
Other silyl groups are also competent for heterocoupling.
Silyloxy groups (1t) effectively yield cross product 3oa. The
slightly larger TBDMS-protected alkyne 1u also couples
effectively to form 3aa upon workup, but the very bulky TIPS-
protected alkyne 1v fails to engage in cross coupling. The
TBDMS group provides a more stable silylpyrrole than the TMS
group, while the Si(OMe)3 group provides additional synthetic
versatility[11] in Hiyama-type couplings.[12]
PhN=NPh
0.5 PhN=NPh
Ph
N
TMS
[TiII]
Me
LnTiIV NPh
2
Ar
Me
reductive
elimination
R
Ph
4
(3 after
hydrolysis)
[2+2] addition
via
Ph
Ph
Me
Ar
R
δ+ δ-
Ph
LnTiIV
Ar
N
N
LnTiIV
N
Table 1. Scope of coupling partners with 1-phenyl-1-propyne (2a)a
LnTiIV
TMS
δ-
Ar
δ+
Me
Me
INT1
Ph
TS1
0.5 PhNNPh
TMS
+
N
1
INT2
H
5% [py2Cl2TiNPh]2
TMS
R
1.1
Ph
2.2
R
alkyne insertion
PhCF3, 115 o
3 h
C
via
R
Ph
TMS
δ-
δ+
HCl workup
δ+
3aa - 3ra
1a-v
2a
Ph
Isolated Yieldb (GC Yield)
TiIV
N
Selectivityc
δ-
R
Ar
Me
Ph
N
Ph
N
Ph
N
Ph
N
TS2
Figure 3. General mechanism and proposed origins of selectivity in cross-
H
H
H
H
selective [2+2+1] pyrrole synthesis.
Chemoselectivity of alkyne insertion into the Ti-C bond of
the azametallacyclobutadiene intermediate INT1 is driven by
alkyne coordination to Ti. Electron-rich alkynes are better ligands
to TiIV Lewis acids, and as such the electron-rich TMS-alkynes
effectively outcompete other alkynes in binding and subsequently
inserting into the metallacycle via TS2 (Figure 3). This can be
observed in reactions of the series of para-substituted
phenylpropynes (Table 2, 3ab-3ae) where alkynes with more
electron-donating groups competed more effectively with
TMSCCR, resulting in more homocoupled arylpropyne products
and thus overall lower selectivity. Further evidence for alkyne
electronics/binding driving 2nd insertion selectivity can be seen in
the competition experiment where the more electron rich p-
substituted TMS aryl alkyne 1f outcompetes the electron deficient
alkyne 1b by 2:1 (Figure 4). Regioselectivity of TMS-alkyne
insertion is likely driven by the a-silyl effect, where the a-SiMe3
moiety stabilizes d- buildup during insertion (Figure 3, TS2),
favoring the metallacycle that places SiMe3 on the a-C. Similar
effects have been observed in the hydroboration of silyl alkynes[14]
and the reactivity of group 4 metal alkyne complexes.[15]
Ph
Ph
Ph
Ph
3ca
71% (90%)
91%
Ph
3aa
3ba
39% (86%)
91%
3da
From TMSC2Ph 1a
(70%)
73% (91%)
89%
F3C
Cl
Br
91%
From tBuMe2SiC2Ph 1uh
Ph
Ph
N
Ph
N
(68%)
N
H
H
H
88%
From iPr3SiC2Ph 1v
(4%)
MeO
Ph
3fa
Ph
3ea
Ph
n.a.
3ga
(45%)
45%
64% (91%)
75% (86%)
89%
93%
MeO
Ph
Me2N
Ph
N
Ph
N
Ph
N
N
H
H
H
H
iPr
Ph
Ph
3ia
Ph
Ph
3ha
73% (82%)
84%
3ja
49% (84%)
86%
3ka
43% (84%)
88%
61% (65%)
84%
Ph
Ph
Ph
Ph
N
N
N
N
N
H
H
H
TMS
Ph
N
TMS
Ph
N
PhCCMe
0.45 PhNNPh
5% [py2Cl2TiNPh]2
Ph
nBu
Ph
H
Ph
Ph
3oa
TMS
+
TMS
Me
Me
3ma’d
3nae
S
From TMSC2nBu 1od
3la
67% (84%)
85%
42% (85%)
+
92% (94%)
68% (77%)
PhCF3, 115 o
C
90%
94%
87%
Ph
Ph
From (MeO)3SiC2nBu 1td
Ph
N
Ph
N
Ph
N
(55%)
55%
H
H
H
Me2N
F3C
NMe2
CF3
4ba : 4fa
1b
1f
1.00 : 1.85
tBu
H
Ph
Ph
Ph
3ra
3paf
12% (73%)
85%
Figure 4. Competition between electronically differentiated TMS-protected
alkynes favors reaction of electron rich alkynes.
3qa
(0%)
n.a.
From TMS2C2 1rg
(44%)
69%
From TMSC2H 1s
(31%)
Directing group effects are observable in reactions with (2-
methoxy)phenyl-TMS-acetylene (1g) and pyridin-2-yl-TMS-
acetylene (1m). 1g gives significant amounts of the 3ga’
regioisomer, and for 1m, 3ma’ is almost exclusively formed, likely
because coordination of the TMS alkyne to Ti via the OMe or 2-
pyridyl groups would enforce the opposite insertion of the TMS-
alkyne into the azametallacyclobutene [2+2] intermediate. (Figure
64%
a0.5 mmol (1.1 eq) 1-phenyl-1-propyne (2a), 1.0 mmol 1 (2.2 eq.), 0.225
mmol PhNNPh (0.5 eq.) and 0.025 mmol [py2Cl2TiNPh]2 (0.05 eq.)) in
2.5 mL CF3Ph heated for 3 hours. Reactions were quenched with 2M
HCl in MeOH to remove the silyl group. bIsolated yield of 3 based on
PhNNPh. cSelectivity against all possible pyrroles; d1.5 h. e1 equiv. of 1.
f4 h. g24 h. h5 h.
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10.1002/anie.201800595
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COMMUNICATION
5). Interestingly, the thiophenyl derivative 1l does not show a
directing effect, presumably due to the hard/soft Ti/S mismatch
making thiophenes weaker donors to Ti.
Ph
0.5 PhNNPh
5% [py2Cl2TiNPh]2
R3
TMS
+
N
R3
H
1.1
R2
2.2
R1
Lewis basic
directing group
PhCF3, 115 o
3 h for 1a
C
R1
R1 = Ph 3ab - 3as
R2
Ph
Ti
Me
via
R1 = Ph 1a
2b-s
1.5 h for 1o
HCl workup
Ph
N
N
R1
=
nBu 1o
Ph
R1 nBu 3ob - 3os
=
Ph
N
N
DG
Ph
Me
Isolated Yieldb (GC Yield)
N
Ti
N
LnTi
Ph
Selectivityc
+
N
TMS
Ph
Me
Me
H
Ph
3ab
3ac
3ad
3aed
23% (57%)
73%
3ga’ and 3ma’
[2+2]
intermediate
TMS
90% (91%)
78% (91%)
93%
H
3oc
65% (77%)
TMS
Ph
N
Ph
Ph
Ph
directing group
inverts TMS alkyne
insertion selectivity!
94%
82%
1m
(similarly, 1g)
N
N
N
H
H
H
3ob
3od
3oe
74% (80%)
94%
87% (91%)
96%
62% (94%)
94%
80% (86%)
88%
Figure 5. Lewis basic groups change the selectivity of 2nd alkyne insertion
through directing effects.
R1
R1
R1
R1
Next, different [2+2] alkyne partners were tested with 1a and
1o (Table 2). Unlike modifications to the TMS-protected alkynes,
electronic and steric modification of the [2+2] alkyne partner alters
the reaction selectivity. For example, electron-donating
phenylpropyne derivatives (3ad, 3od, 3ae, 3oe). decrease the
yield and chemoselectivity of second insertion, resulting from an
increase in the formation of homocoupled arylpropyne pyrroles.
This highlights the importance of alkyne precoordination during
the alkyne 1,2 insertion step, where now the electron-donating
arylpropyne can more effectively compete with the electron-rich
TMS-protected alkynes. Consistent with this, reaction of 2-
methoxyphenyl propyne (2f), which can precoordinate to Ti
through the ether moiety, leads predominantly to homocoupling of
2f instead of heterocoupled 3af. Ortho-steric hindrance on aryl
propynes (3ag-3ai, 3og-3oi) significantly lessens conversion and
regioselectivity of [2+2] cycloaddition. Prolonged reaction time
does not increase conversion, indicating catalyst death in these
cases.
CF3
Cl
OMe
NMe2
3agd
(32%)
72%
3ahd
(16%)
Ph
51%
H
3ohd
3aid
(41%)
77%
3af
(18%)
30%
Ph
Ph
N
Ph
N
N
N
H
H
H
3ogd
26% (63%)
74%
3oie
42% (70%)
76%
(25%)
45%
R1
R1
R1
iPr
R1
MeO
3aj
64% (84%)
87%
H
3oj
3ak
79% (79%)
82%
H
3ok
3al
(0%)
n.a.
3ame
46% (80%)
91%
Ph
Ph
Ph
Ph
N
N
N
N
nBu
H
H
3ol
(0%)
n.a.
3omf
73% (91%)
94%
79% (91%)
91%
61% (87%)
90%
R1
R1
R1
R1
N
S
3and
(12%)
n.a.
3aog
(88%)
3apg
65% (94%)
95%
Ph
N
Ph
N
Ph
N
nPr
iPr
88%
H
H
H
Table 2. Scope of coupling partners with 1a and 1o.a
3oog
49% (90%)
91%
3opg
70% (99%)
99%
3ond
(30%)
n.a.
nPr
R1
R1
R1
3arg,h
(42%)
43%
3aqe,g
56% (70%)
96%
3asg
(4%)
n.a.
Ph
Ph
Ph
N
N
N
H
H
H
Ph
3org,h
(50%)
51%
3osg
(0%)
n.a.
3oqf,g
57% (87%)
90%
R1
R1
R1
iPr
tBu
Ph
a0.5 mmol (1.1 eq) 2, 1.0 mmol 1a or 1n (2.2 eq.), 0.225 mmol PhNNPh (0.5 eq.)
and 0.025 mmol [py2Cl2TiNPh]2 (0.05 eq.)) in 2.5 mL CF3Ph heated for 1.5 or 3
hours. bIsolated yield of 3 based on PhNNPh. GC yields in parenthesis.
f
cSelectivity against all possible pyrroles. d48 h. e24 h. 6 h. g(THF)3I2TiNPh (10
mol %) used as catalyst. h4 h.
Differing aromatic substituents (3ai, 3oi, 3ak, 3ok) are also
tolerated, although now pyridine substitution (3al and 3ol)
completely inhibits catalysis through coordination to Ti. Longer
alkyl substituents (3am, 3om) also work well, but bulkier isopropyl
substituents (3an, 3on) do not undergo facile [2+2] cycloaddition.
Reactions of unactivated dialkyl/diaryl internal alkynes (3ao-3ar,
3oo-3or) require the more Lewis acidic (THF)3I2TiNPh. However,
alkynes with little electronic differentiation, like 4-methyl-2-
pentyne (3ar, 3or), yield products of unselective [2+2]
cycloaddition, and bulky internal alkynes (3as, 3os) are
unreactive.
The advantage of the silyl directing group is its ability to be
functionalized after reaction. Although poor partners for cross
coupling reactions, 2-TMS pyrroles can undergo facile
electrophilic aromatic substitution. For example, NBS substitution
of the TMS group yields bromopyrroles in high yield, which
provides a versatile handle for further pyrrole functionalization
(Figure 6, top).
Furthermore, this alkyne heterocoupling strategy can
provide facile access to the pyrrole core of lamellarins, a class of
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10.1002/anie.201800595
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COMMUNICATION
(5) Amarnath, V.; Anthony, D. C.; Amarnath, K.; Valentine, W. M.; Wetterau, L.
A.; Graham, D. G. J. Org. Chem. 1991, 56, 6924-6931.
(6) (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev.
2013, 113, 3084-3213; (b) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem.
Soc. Rev. 2014, 43, 4633-4657.
marine natural products. We have completed a short formal
synthesis of lamellarin R. In situ benzylic oxidation of 6wd with 2-
iodoxybenzoic acid (IBX) (6wd was generated from the [2+2+1]
coupling of 1w, 2d and 4,4’-azodianisole) yields 7wd, which can
then be deprotected by tetrabutylammonium fluoride and water to
the aldehyde 8wd, intersecting a previous synthesis reported by
Jia[16] (Figure 6, bottom).
(7) (a) George, J.; Kim, H. Y.; Oh, K. Org. Lett. 2017, 19, 628-631; (b) Men, Y.;
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10.1021/acs.orglett.7b04007.
In-situ bromination of TMS pyrroles:
Ph
N
1.) 0.45 PhNNPh
5% [py2Cl2TiNPh]2
PhCF3, 115 o
TMS
+
Me
Br
C
Me
2
2.) 2.2 eq NBS
(1-pot, in situ)
Ph
Ph
Ph
Ph
5aa
56%
1a
2a
[2+2+1] strategy in the formal synthesis of Lamellarin R:
Ar
1.) 0.5 ArNNAr
2.5% [py2Cl2TiNPh]2
PhCF3, 115 o
O
TBDMS
Me
N
TBDMS
C
3
+
2.) 4.4 eq. IBX
(1-pot, in situ)
Ar
Ar
Ar
Ar
1w
2d
7wd
(9) (a) Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Nat Chem 2016, 8, 63-68; (b) Davis-
Gilbert, Z. W.; Yao, L. J.; Tonks, I. A. J. Am. Chem. Soc. 2016, 138, 14570-
14573; (c) Davis-Gilbert, Z. W.; Tonks, I. A. Dalton Trans. 2017, 46, 11522-
11528.
Ar = p-OMePh
1.) 1.5 eq. TBAF
THF, 30 min
2.) H2O
OH
OMe
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Chem. Int. Ed. 2013, 52, 5355-5359; (d) Ricker, J. D.; Geary, L. M. Top. Catal.
2017, 60, 609-619.
3 steps
(Jia)16
O
O
N
N
Lamellarin
R
O
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DeShong, P. Org. Lett. 1999, 1, 2137-2140.
8wd
24% overall yield
OH
OMe
HO
MeO
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Figure 6. Further elaboration of TMS pyrroles. Top: bromination
of 2-TMS-pyrroles. Bottom: formal synthesis of lamellarin R.
In summary, we have found that the we can exploit the
electronic properties of silyl-substituted alkynes to perform highly
chemo- and regioselective [2+2+1] heterocouplings to form
pyrroles. The products, 2-silyl-pyrroles, can be further
functionalized and provide access to a large range of tetra- and
pentasubstituted pyrroles, yielding diverse N-arylated pyrroles
that map onto several natural product cores. Going forward, we
plan on exploiting this and related types of electronic control to
further advance chemo- regioselective Ti-catalyzed oxidative
amination reactions beyond pyrrole synthesis.
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Acknowledgements
Financial support was provided by the National Institutes of
Health (1R35GM119457). The Chemistry Department NMR
facility is supported through a grant from the National Institutes
of Health (S10OD011952) with matching funds from the
University of Minnesota. IAT is a 2017 Alfred P. Sloan Fellow.
Keywords: Pyrrole • Titanium • Cycloaddition • Alkyne •
Selectivity
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2011, 7, 442-495.
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10.1002/anie.201800595
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Title
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COMMUNICATION
Ph
N
TMS
R2
Author(s), Corresponding Author(s)*
TMS
δ-
δ+
R1
δ+
Ph
R2
cat. Ti
TiIV
+
TMS
R2
N
PhN=NPh
[2+2+1]
Page No. – Page No.
R1
R3
δ-
R3
Title
R1
10 possible pyrrole products
up to 99% chemo- & regioselectivity
> 50 examples
R3
R1 = alkyl, aryl
vinyl, TMS, H
R2, R3
=
via
alkyl, aryl
E Pluribus Unum: Trialkylsilyl-protected alkynes enable highly chemo- and
regioselective reactions in Ti-catalyzed [2+2+1] multicomponent pyrrole synthesis.
The resulting pentasubstituted 2-SiR3 pyrroles are formed with up to 99% selectivity
over the other 9 possible pyrrole products.
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