Dative Directing Group Effects in Ti-Catalyzed [2+2+1] Pyrrole Synthesis: Chemo- and Regioselective Alkyne Heterocoupling

Article abstract of DOI:10.1021/acscatal.8b04669

Transient dative substrate-Ti interactions have been found to play a key role in controlling the regioselectivity of alkyne insertion and [2+2] cycloaddition in Ti-catalyzed [2+2+1] pyrrole synthesis and Ti-catalyzed alkyne hydroamination. TMS-protected a

Full text of DOI:10.1021/acscatal.8b04669

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Article
Dative Directing Group Effects in Ti-Catalyzed [2+2+1] Pyrrole
Synthesis: Chemo- and Regioselective Alkyne Heterocoupling
Hsin-Chun Chiu, Xin Yi See, and Ian A. Tonks
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04669 • Publication Date (Web): 29 Nov 2018
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ACS Catalysis
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Dative Directing Group Effects in Ti-Catalyzed [2+2+1] Pyrrole Syn-
thesis: Chemo- and Regioselective Alkyne Heterocoupling
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Hsin-Chun Chiu, Xin Yi See, and Ian A. Tonks*
Department of Chemistry, University of Minnesota−Twin Cities, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United
States
Supporting Information Placeholder
method has further been applied to the formal synthesis of Prostaglan-
din A2.23 Removable directing groups have also been used in the Pau-
son-Khand reaction, notably by using silicon-tethered pyridinyl vinyl
silanes which could go through facile hydrolytic desilylation.24-25
ABSTRACT:
Transient dative substrate-Ti interactions have been
found to play a key role in controlling the regioselectivity of alkyne in-
sertion and [2+2] cycloaddition in Ti-catalyzed [2+2+1] pyrrole syn-
thesis and Ti-catalyzed alkyne hydroamination. TMS-protected alkynes
with pendent Lewis basic groups can invert the regioselectivity of TMS-
protected alkyne insertion, leading to the selective formation of highly
substituted 3-TMS pyrroles. The competency of various potential di-
recting groups was investigated, and it was found that the directing
group effect can be tuned by modifying the catalyst Lewis acidity, the
directing group basicity, or the directing group tether length. Dative di-
recting group effects are unexplored with Ti catalysts, and this study
demonstrates the potential power of dative substrate-Ti interactions in
tuning selectivity.
Pendent alkoxide directing groups have been used extensively in
Ti-catalyzed and mediated reactions to engender regio-, chemo- and en-
antioselective transformations.26 For example, Sharpless’ catalytic asym-
metric alkene epoxidation relies on alkoxide directing groups to engen-
der enantiofacial selectivity,27 while more recently Micalizio has used
alkoxides to direct alkyne insertion regioselectivity in Ti-mediated re-
ductive coupling reactions (Figure 1, middle)18-19, 28-31 and Burns has
used alkoxides to direct stereoselective alkene dihalogenation and halo-
azidation reactions.32-35 Alkoxide-directed coupling reactions have also
served as a platform for heterocycle syntheses, such as pyridines and in-
dolizidines.36-37
KEYWORDS: directing group effects, multicomponent reactions, pyr-
roles, titanium, alkynes
Previous work: electronically-controlled [2+2+1] cross coupling:
Introduction
Ph
R2
TMS
TMS
δ-
δ+
R1
cat. [Ti]
δ+
Ph
R2
N
+
Highly substituted pyrroles are important components of many bio-
active natural products, drug candidates, and FDA-approved drugs.1-4
Recently, we have reported several multicomponent formal [2+2+1]
pyrrole syntheses from alkynes and diazenes or azides (Figure 1).5-9
These methods provide facile, modular access to highly substituted pyr-
role cores that are otherwise challenging to synthesize.
TMS
R2
TiIV
N
PhN=NPh
[2+2+1]
R1
R3
δ-
R3
R1
R3
via
Prior art: anionic directing groups
anionic
directing group
5% Ti(OiPr)4
7.4% (+)-DET
tBuOOH
O
OH
OH
Attaining regio- and chemoselectivity can be inherently difficult
[2+2+1] cycloaddition reactions such as our Ti-catalyzed pyrrole syn-
thesis or the Pauson-Khand reaction.10-11 Previous studies demonstrated
that the selectivity of Ti-catalyzed alkyne coupling is driven by intrinsic
alkyne stereoelectronic properties, and this substrate-driven selectivity
results in a statistical mixture of regioisomers.5 More recently we discov-
ered that the heterocoupling of TMS-protected alkynes can occur with
exceptional regioselectivity, yielding 2-TMS pyrroles (Figure 1, top).8
These reactions are highly selective due to the electronic properties of
the TMS-protected alkynes: they do not easily undergo the [2+2] cy-
cloadditions with Ti=NR imidos, but rapidly (because of their electron-
richness) and regioselectively (because of the thermodynamic a-Si ef-
fect8, 12-19) insert into azatitanacyclobutenes. This protocol can access all
possible penta- and tetrasubstituted pyrrole substitution patterns except
for 1,2,3,5-tetrasubstitution.
4 Å M.S. -20 o
C
95% yield,
91% ee
anionic
Asymmetric epoxidation
directing group
ClTi(OiPr)3
c-C5H9MgCl
LiO
Ph
OH
Ph
+
68% yield
rs > 42:1
PhMe
Li-alkoxide
added after
Ph
Ph
Metallacycle-mediated
cross coupling
This work: inverted regioselectivity through directing effects
Ph
R2
TMS
DG
cat. [Ti]
Ph
R2
N
+
DG
R2
TiIV
N
PhN=NPh
[2+2+1]
R3
DG
TMS
DG = Lewis basic
R3
TMS
R3
via
dative directing group
An alternative strategy for regiocontrol is to use heteroatom-based di-
recting groups to enforce selectivity. For example, sulfur and nitrogen-
substituted alkenes have been used in the cobalt catalyzed [2+2+1] Pau-
son-Khand reaction to direct the product regioselectivity.20-22 This
Figure 1. Top: general overview of directing groups in Ti catalyzed/me-
diated chemistry; Bottom: Ti-catalyzed [2+2+1] pyrrole synthesis and
methods for chemo- and regioselective alkyne heterocoupling.
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8
To exert complete regiocontrol over multisubstituted pyrrole
synthesis, we have undertaken a study of pendent directing group effects
in Ti-catalyzed [2+2+1] pyrrole synthesis (Figure 1, bottom), envision-
ing that it would be possible to reverse the regiochemical course of the
reaction. In contrast to anionic directing groups, the use of dative direct-
ing groups in titanium catalysis is unexplored. However, we envisioned
that transient dative donor interactions could promote chemo- and re-
gioselective reactions while also undergoing the facile ligand exchange
needed for productive redox catalysis. We herein report that TMS-
protected alkynes with pendent Lewis basic groups can invert the regi-
oselectivity of TMS-protected alkyne insertion in Ti-catalyzed [2+2+1]
pyrrole synthesis. This demonstrates that a dative directing group effect
can override the substrate’s intrinsic selectivity. These reactions lead to
the formation of 3-TMS-substituted pyrroles, which can be used in com-
plex molecule synthesis.
Table 1. Optimization of reaction conditions to promote directed
alkyne insertion.a
Ph
Ph
TMS
Me
Y% THF3TiI2(NPh)
0.5 PhNNPh
X equiv.
N
N
Ar
TMS
Me
Me
+
+
PhCF3, T o
C
Ph
TMS
3a-TMS
Ph
Ar
4a-TMS
Ph
OMe
1a
2a
Entry
T
X
Time
(h)
2
Y
Yield of
3ab (%)
51
Ratio of
3a/4ab
1.1
9
(
℃
)
eq.
2
(%)
10
10
10
10
10
10
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1c
2
3
4
5
6
7
115
115
80
2
1
76
5.5
2
1
81
7.2
60
2
2
79
8.8
60
1
2
67
9.3
45
2
24
24
74
10.5
10.3
Results and Discussion
45
1
74
aA mixture of 0.1-0.2 mmol 1a, 0.1 mmol 2a, 0.225 mmol PhNNPh, 0.0025-
0.01 mmol (THF)3TiI2(NPh) and 0.01 Ph3CH (internal standard) in 0.5 mL
CF3Ph were heated at desired temperature and time. bYield and selectivity are
Unlike other TMS-protected alkynes, the [2+2+1] heterocou-
plng of ((2-methoxyphenyl)ethynyl)trimethylsilane (1a) with phe-
nylpropyne (2a) was remarkably unselective for 4a-TMS, giving a 1.1:1
ratio of 3a-TMS:4a-TMS (Table 1, Entry 1).8 We speculated that the
increased yield of 3a-TMS was a result of the o-OMe group precoordi-
nating to Ti and directing 2nd alkyne insertion in a manner opposite the
electronic properties of the alkyne (Figure 2).
c
determined by 1H NMR and reported with respect to 2a. Reported in Ref 8
with [py2TiCl2(NPh)]2 as catalyst.
First, substrates containing O-atom donors (1a-
1h) were tested.
Substrates that can form 5 membered chelates upon 2nd insertion such
as 1a, vinyl methyl ether 1b, and homopropargylic ethers 1c and 1d are
excellent directing groups with the more Lewis acidic catalyst
THF3TiI2(NPh) (Condition A), giving high regioselectivity and yields
of pyrroles 3a-3d. Directing group effects are observed whether the 2-C
Ph
N
Ph
N
TMS
Me
5% [py2TiCl2(NPh)]2
0.5 PhNNPh
2 equiv.
Ar
TMS
Me
Me
+
+
PhCF3, 115 oC, 3 h
Ph
2a
TMS
Ph
Ar
Ph
OMe
3a-TMS
4a-TMS
1a
51%
45%
linker is sp2 (1a
, , -
1b) or sp3 (1c
1d) hybridized. Substrates 1b 1d are sig-
TMS
O
nificantly less selective with the less Lewis acidic catalyst
[py2TiCl2(NPh)]2, although in the case of 1d acceptable regioselectivity
for 3d is still obtained. Phenyl ether 1h, which also contains a 2-C linker,
manifests no directing group effect—presumably due to a combination
of the weaker aryl ether donor O and increased rotational degrees of
freedom.
δ-
δ+
Ph
Ph
TiIV
TiIV
N
N
δ+
δ-
Ar
TMS
Ph
Me
Ph
Me
3a-TMS: Directed
4a-TMS: Electronically
Controlled 2nd Insertion
2nd Insertion
Figure 2. Initial observation of a directing group effect: o-Me substituted
aryl alkynes (1a) have poor selectivity for electronically preferred 2nd in-
In contrast to 2-C linkers, shorter (1-C) linkers such as propar-
gylic ethers (1e) and acetals (1f) do not yield productive reactivity due
to C-O bond decomposition.40 Longer (3-C) linkers (1g) display no di-
recting group effect, but are still competent for heterocoupling to the 2-
unsubstituted pyrrole (4g).
sertion product 4a-TMS
.
Thus, we sought to find conditions that favored the directed 3-
TMS product 3a-TMS. First, [py2TiCl2(NPh)]2 was replaced by the
more Lewis acidic catalyst THF3TiI2(NPh)38-39 to promote stronger co-
ordination of the o-OMe group. This increased the 3a-TMS:
4a-TMS ra-
tio to 5.5:1 (Table 1, Entry 2). Lowering the reaction temperature fur-
ther improved the selectivity, giving regioisomeric ratios > 10.5:1 (Table
1, Entries 2-5). At lower temperatures dissociation of the o-OMe is likely
slowed, resulting in formation of the kinetically preferred metallacycle
leading to 3a-TMS over 4a-TMS.8 In our previous studies of TMS-
alkyne heterocouplings, chemoselectivities were good at a 1:1 ratio of
the two alkynes, but from a practical perspective we found it better to
use an excess of the TMS-alkyne in order to make product separations
more simple. However, here reducing the equivalents of 1a had little ef-
fect on yield or selectivity, indicating that the directing group effect can
more effectively outcompete 2a homocoupling (Entry 6). Thus, the
conditions in entry 6 were deemed optimized.
Next, other Lewis basic heteroatom donors were examined.
Arenes with an ortho –SMe (1i) or –NMe2 (1j) couple with high regi-
oselectivity to the directed products 3i and 3j. The less basic and softer
–SMe group (1i) directed to higher regioselectivity (20:1) than harder
–OMe (1a, 9.3:1) and –NMe2 (1j, 8.0:1), which is unexpected due to
the preference of TiIV for harder ligands. Given the sensitivity to chelate
size observed with O-atom donors, the increased regioselectivity in 1i
may be a function of the S atomic size and resulting chelate angles of the
S-containing ring.
Tertiary aryl amine 1j displays good directing ability, although al-
iphatic pendent tertiary amines (1l,
1n) do not. This may be due to an
increase in tether flexibility coupled with the sterics of the 3° amine.
Nonetheless, these substrates do not inhibit catalysis and are selective
for heterocoupling to products 4l and 4n. Aryl fluorides (1k), alkyl thi-
oethers (1m), and thioacetals (1o) give high yields of the non-directed
products 4k,
4m, and 4o with [py2TiCl2(NPh)]2, which is more func-
tional group tolerant than THF3TiI2(NPh) owing to reduced Lewis
acidity.
The directing effect was explored on a range of TMS-protected
alkynes with pendent Lewis basic functionality (Table 2). The opti-
mized conditions from Table 1 were used (Condition A), along with the
prior conditions for TMS-alkyne heterocoupling catalysis8 (Condition
B).
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Table 2. Scope of directing group effects in Ti-catalyzed [2+2+1] pyrrole synthesis.
1
2
3
4
Ph
N
Ph
N
Condition Aab
10% THF3TiI2(NPh), X = 1
0.5 PhNNPh
PhCF3, 60 oC, 2 h
(More Lewis Acidic)
Condition Bb
5% [py2TiCl2(NPh)]2, X = 2
0.5 PhNNPh
PhCF3, 115 oC, 3 h
(Less Lewis Acidic)
R1
+
Me
1.) Conditions A or B
R1
Me
Me
or
X equiv.
TMS
2.) 2 M HCl(aq) Workup
Ph
3a-u
1 4a-u
Ph
Ph
1a-u
2a
R
% Isolated Yield (% NMR)c
5
Ratio 3 : 4
6
Directing effect observed:
O-Atom Donors:
7
8
9
OMe
BnO
Ph
Ph
Condition A
Condition B
NR
Condition A
64% (67% NMR)
9.2 : 1 3a : 4a
Condition B
(51% NMR)
1.1 : 1 3a : 4a
BnO
NR
N
N
Me
Me
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1e
3e
1a
3a
TMS
TMS
Ph
Ph
OMe
Ph
N
O
Ph
N
Condition Ad
40% (69% NMR)
6.3 : 1 3b : 4b
Condition Bd
(25% NMR)
0.6 : 1 3b : 4b
Condition A
Condition B
NR
O
O
NR
O
Me
Me
OMe
1b
1c
1d
3b
1f
3f
TMS
TMS
TMS
TMS
TMS
TMS
Ph
Ph
OBn
OMe
BnO
Ph
N
Ph
N
Condition A
(20% NMR)
Only 4g
Condition B
87% (90% NMR)
Only 4g
Condition A
76% (82% NMR)
41 : 1 3c : 4c
Condition B
(59% NMR)
2.2 : 1 3c : 4c
3
Me
Me
OBn
OMe
1g
3c
4g
BnO
Ph
Ph
3
Ph
N
Ph
N
Condition A
(17% NMR)
Only 4h
Condition B
10% (81% NMR)
Only 4h
Condition A
58% (68% NMR)
14 : 1 3d : 4d
Condition B
(73% NMR)
5.2 : 1 3d : 4d
Me
Me
OPh
PhO
3d
1h
4h
Ph
Ph
Other Heteroatomic Donors:
Directing effect observed:
SMe
Ph
N
nBuS
Ph
N
Condition A
(8.5% NMR)
Only 4m
Condition B
35% (81% NMR)
Only 4m
Condition A
34% (82% NMR)
20 : 1 3i : 4i
Condition B
(66% NMR)
2.4 : 1 3i : 4i
Me
Me
SMe
1i
3i
1m
Bn2N
4m
nBuS
TMS
TMS
Ph
Ph
NMe2
Ph
N
Ph
N
Condition Ad
29% (71% NMR)
8.0 : 1 3j : 4j
Condition Bd
(73% NMR)
5.6 : 1 3j : 4j
Condition A
(11% NMR)
Only 4n
Condition B
11% (83% NMR)
Only 4n
Me
Me
NMe2
1j
3j
1n
4n
TMS
TMS
TMS
Bn2N
Ph
Ph
S
Ph
N
Ph
N
Condition A
(7.7% NMR)
Only 4k
Condition B
57% (76% NMR)
Condition A
(17% NMR)
Only 4o
Condition B
72% (84% NMR)
Only 4o
S
Me
Me
Only 4k
F
F
1k
1o
4k
4o
S
Ph
Ph
TMS
TMS
Ph
S
Condition A
(18% NMR)
Only 4l
Condition B
57% (85% NMR)
Only 4l
N
Me
NBn2
Bn2N
1l
4l
Ph
Heterocyclic Donors:
Directing effect observed:
Me
N
Ph
Ph
N
Condition Ae
(6% NMR)
-
Condition Be
68% (77% NMR)
19 : 1 3p : 4p
Condition Ae
Condition Be
NR
N
N
NR
N
N
O
S
N
Me
Me
N
Me
1p
3p
1s
3s
TMS
TMS
TMS
TMS
TMS
Ph
Ph
S
Ph
N
Ph
N
Condition Ae
38% (62% NMR)
5.2 : 1 3q : 4q
Condition Be
(19% NMR)
0.5 : 1 3q : 4q
Condition A
(4.4% NMR)
Only 4t
Condition B
41% (67% NMR)
Only 4t
N
N
N
Me
Me
S
1q
3q
1t
4t
Ph
O
S
Ph
Ph
N
Condition A
(5.4% NMR)
Only 4u
Condition B
67% (84% NMR)
Only 4u
O
Ph
N
Condition Ae
(14% NMR)
2.7 : 1 3r : 4r
Condition Be
(3.3% NMR)
0.2 : 1 3r : 4r
N
Me
Me
O
1u
4u
Ph
1r
3r
TMS
Ph
aCondition A: A mixture of 0.5 mmol 1 (1.1 eq.), 0.5 mmol 2 (1.1 eq), 0.225 mmol PhNNPh (0.5 eq.) and 0.05 mmol THF3I2Ti(NPh) (0.1 eq.) in 2.5 mL CF3Ph
was heated for 2 hours. Reactions were quenched with 2 M HCl in MeOH; bCondition B: A mixture of 1.0 mmol 1 (2.2 eq.), 0.5 mmol 2 (1.1 eq), 0.225 mmol
PhNNPh (0.5 eq.) and 0.025 mmol [py2Cl2TiNPh]2 (0.05 eq.) in 2.5 mL CF3Ph was heated for 3 hours. Reactions were quenched with 2 M HCl in MeOH; c
1Isolated and/or NMR yield of major regioisomer drawn and are reported with respect to 2a. dReaction run at 80 °C; eReaction run at 115 °C.
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Heterocyclic substituent reactivity is strongly dependent on the
Page 4 of 9
ethers like that in 5y do not serve as directing groups in the [2+2+1] re-
action, but o-Me derivative 1y is a deprotectable surrogate. Directed
[2+2+1] heterocoupling of 1y with 2a and (p-BrPh)2N2 gives methoxy-
protected 3y, which can be deprotected to phenol 4y prior to benzyla-
tion to 5y in 22% overall yield (Figure 5). The advantage of this protocol
is that the [2+2+1] reaction is widely tolerant of substitution on both
azobenzene7 and alkyne8 fragments, allowing access to diverse structures
with relative ease.
heterocycle basicity.41 N-methylimidazole (1s) is too basic and inhibits
catalysis for both THF3TiI2(NPh) and [py2TiCl2(NPh)]2 reactions
through coordination to Ti. Pyridine (1p), which is a reasonably strong
heterocyclic base but less basic than 1s, inhibits catalysis with the more
Lewis acidic THF3TiI2(NPh), but acts as a directing group and yields
high regioselectivity (19:1) with [py2TiCl2(NPh)]2. Thiazole (1q),
which is less basic than pyridine, acts as a selective directing group
(5.2:1) with THF3TiI2(NPh), but not with the less Lewis-acidic
[py2TiCl2(NPh)]2 (0.5:1). Benzoxazole (1r), which is similar to thia-
zole 1q in basicity, yields similar selectivities but poor yields due to C-O
1
2
3
4
5
6
7
8
Br
Br
MeO
Br
9
Me
1.) 2.5% THF TiI (NPh)
Br
3
2
PhCF3, 60 oC, 30 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
bond cleavage, similar to other propargylic O-functional groups (1e,
1f).
+
+
0.5
N
N
N
Very weakly basic furan (1t) and thiophene (1u) pendants are not
strong enough to serve as directing groups with either catalyst but still
2.) 2 M HCl(aq)
not purified/isolated
Me
TMS
Ph
1y
2a
OMe
3y
yield normal heterocoupled products 4t and 4u
.
H
Ph
Br
2 equiv. LiI
Internal alkyne 1w is also suitable for directed heterocoupling,
giving 3w in moderate yield (Figure 3). This takes advantage of the ex-
treme sensitivity of [2+2] cycloaddition to substrate sterics as well as the
directing group effect in 2nd alkyne insertion. However, the window for
success is narrow: less sterically encumbered alkynes (1v) predomi-
nantly homocouple due to their higher reactivity, while more sterically
encumbered internal alkynes (1x) are too hindered even for 2nd inser-
tion, and thus yield mainly pyrrole products of PhCCMe homocoupling.
2,4,6-collidine
175 oC, 30 h
Br
F
not purified/isolated
Br
F
Br
Br
Br
0.8 equiv.
N
Me
1.5 equiv. K2CO3
MeCN, reflux
N
Me
O
5y
H
Ph
OH
4y
22%
overall yield
from 1y
H
Ph
F
Ph
Ph
R
Me
10% THF3TiI2(NPh)
0.5 PhNNPh
F
N
N
Ar
Ar
Me
Me
or
+
PhCF3, 60 oC, 3 h
Figure 5. Synthesis of an EP1 antagonist derivative 5y
.
Ph
2a
3w
3x
iPr
tBu
Ph
52% (59% NMR)
for R = Me, mainly 1v homocoupled pyrrole
Ph
In addition to alkyne insertion, directing group effects can also be
seen during the [2+2] cycloaddition step (Figure 6). For example, reac-
tion of 1z under catalytic conditions results in exclusive formation of 6z
In contrast, the reaction of 1-phenylpropyne gives a mixture of all 3 pos-
sible regioisomers.5,7, 45-47 Since 1z has little steric or electronic bias for
[2+2] cycloaddition or insertion, it is likely that the –OMe group directs
the [2+2] cycloaddition. Similarly, reaction of 1v results exclusively in
OMe
low conversion
R = Me 1v
iPr 1w
.
tBu 1x
Figure 3. Directing group effects on internal alkyne heterocoupling.
Other internal alkynes can also serve as [2+2] partners along with
directing group-tethered TMS alkynes. For example, reaction of 3-
hexyne (2b) maintains good chemo- and regioselectivity to form 3ab
,
formation of 6v
.
albeit with a longer reaction time (Figure 4, top). Additionally, internal
alkynes with appended directing groups such as 1v—which typically
would undergo rapid homocoupling (vide supra)—can be heterocou-
pled with TMS alkynes with pendent strong directing groups such as 1p
to form products such as 3pv (Figure 4, bottom). Unfortunately, all het-
erocoupling attempts with terminal alkynes have failed; these alkynes
appear to be too reactive and instead undergo either alkyne trimeriza-
tion or pyrrole formation via homocoupling.
OMe
Ph
N
Double-Directed Selective Coupling:
Me
Ph
N
MeO
5% [py2TiCl2(NPh)]2
0.5 PhNNPh
R1
nBu
Me
MeO
6v
46% (79% NMR)
2
or
PhCF3, 115 oC, 3 h
R2
nBu
6z
OMe
1v or 1z
62% (91% NMR)
Ph
Undirected, Unselective Coupling:
Ph
Ph
10% py3TiCl2(NPh)
Me
MeO
1.) 10% THF3TiI2(NPh)
0.5 PhNNPh
PhCF3, 60 oC, 16 h
N
N
N
Ph Me
Me
Ph
Ph
+
Me
Ph
N
0.5 PhNNPh
Et
2
+
PhCF3, 110 oC, 16 h
Et
+
Ph
Me
Ph
Me
Ph
Ph
Me
2.) 2M HCl(aq)
TMS
Et
OMe
18%
41%
32%
1a
2b
3ab
Et
Figure 6. Substrate-directed regioselective pyrrole formation via alkyne
homocoupling.
38% (71% NMR)
7.2 : 1 3ab : 4ab
Having established that directing groups can influence the regio-
chemistry of [2+2] cycloaddition, the possibility of performing sub-
strate-directed Ti-catalyzed alkyne hydroamination was explored.48 Re-
action of electronically unbiased substrate 1z with aniline resulted in se-
lective formation of 7z, after directed [2+2] cycloaddition and proto-
nolysis of the metallacycle by aniline (Figure 7). This reaction repre-
sents the first example of Ti-catalyzed directed alkyne hydroamination,
and yields electronically unbiased dissymmetric ketones that are difficult
to synthesize selectively via Wacker oxidation of internal alkenes.49-54 It
is notable that weakly Lewis-basic dialkyl ether of 1z is capable of direct-
ing selective alkyne [2+2] cycloaddition despite stoichiometric quanti-
ties of aniline.
1.) 5% [py2TiCl2(NPh)]2
0.5 PhNNPh
PhCF3, 115 oC, 3 h
Ph
N
Me
N
Me
OMe
2
+
N
1p
2.) 2M HCl(aq)
TMS
3pv
OMe
65% (67% NMR)
1v
3pv only
Figure 4. Directed heterocoupling with other internal alkyne [2+2] part-
ners.
[2+2+1] directed heterocoupling can enable facile synthesis of
pyrrole-containing EP1 antagonist derivatives (Figure 5).3, 42-44 These
moieties are typically synthesized through classical Paal-Knorr synthe-
ses, and require multistep pyrrole construction followed by post-func-
tionalization of the pyrrole core to introduce more intricate substitution
patterns42-43 such as the 2-methyl-1,3,5-triaryl core of 5y. Benzyl aryl
ACS Paragon Plus Environment

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ACS Catalysis
Example Reaction Condition Optimization (Table 1).
via
1.) 20% Ti(NMe2)4
3 equiv. PhNH2
O
O
O
1
2
3
4
Ti
N
Ph
Example for Entry 2: In a glovebox, to an NMR tube was added
PhNNPh (8.2 mg, 0.045 mmol, 0.5 eq.), (THF)3I2TiNPh (6.1 mg,
0.01 mmol, 0.11 eq.), ((2-methoxyphenyl)ethynyl)trimethylsilane
O
PhCF3, 115 oC, 24 h
2.) 2 M HCl, 3 h
nBu
n
nBu
Bu
1z
7z
Only Regioisomer
(
1a) (20.4 mg, 0.1 mmol, 1.1 eq.), phenylpropyne (2a) (11.6 mg,
67% (78% NMR)
0.1 mmol, 1.1 eq.), triphenylmethane (4.9 mg, 0.02 mmol, 0.22
eq.) as the internal standard, and 0.5 mL PhCF3. The NMR tube
was sealed and brought out of the glovebox, and a t = 0 h No-D 1H
NMR spectrum was taken. The NMR tube was heated at 115 °C in
an oil bath. No-D H NMR spectra were taken every 15 minutes
until the full consumption of PhNNPh. Yields are reported with re-
5
6
7
8
Figure 7. Substrate-directed regioselective alkyne hydroamination.
Conclusions
In summary, we have shown that TMS-protected alkynes with
pendent Lewis basic groups can invert the regioselectivity of TMS-
protected alkyne insertion, leading to selective formation of highly sub-
stituted 3-TMS pyrroles. This method provides a complementary ap-
proach to regioselective [2+2+1] pyrrole formation and also demon-
strates how dative substrate-Ti interactions can influence—and, im-
portantly, tune—regioselectivity through directing group effects, which
was previously unexplored in Ti catalysis.
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
spect to 2a
.
Example Synthesis and Isolation of Multisubstituted Pyrroles via Heter-
ocoupling Reactions (Table 2, Condition A).
Example for ((2-methoxyphenyl)ethynyl)trimethylsilane (1a): In
a glovebox, to a 7 mL vial was added PhNNPh (41.0 mg, 0.225
mmol, 0.5 eq.), (THF)3I2TiNPh (30.5 mg, 0.05 mmol, 0.11 eq.),
((2-methoxyphenyl)ethynyl)trimethylsilane (1a) (102 mg, 0.5
mmol, 1.1 eq.), phenylpropyne (2a) (58.0 mg, 0.5 mmol, 1.1 eq.),
and 2.5 mL PhCF3. The reaction was then sealed with a Teflon
screw cap and heated at 60 °C outside of the glovebox in an oil bath
for 2 hours. The reaction was diluted by 2 mL ethyl acetate,
quenched by 2 mL 2M HCl in methanol for 1 hour, washed with
DI water, dried over Na2SO4 and concentrated prior to purifica-
tion. The product 3a was isolated by silica gel chromatography us-
ing 5% EA/Hex eluent to give a pale-yellow oil. (120 mg, 64% cor-
The inverse regioselectivity highly depends on the coordinating
strength of the functional groups, the tether length, and the Lewis acidity
of the Ti catalyst. These effects work in concert, providing a high degree
of tunability of the pyrrole regiochemistry. Balancing the directing group
Lewis basicity with the catalyst Lewis acidity is critical for catalysis: too
strong of an acid-base pairing inhibits catalysis, while too weak of a pair-
ing results in formationof 2-TMS pyrrole
4
instead of the 3-TMSpyrrole
3
. Further, we have shown that dative directing group effects can also
play a role in other Ti-catalyzed reactions such as alkyne hydroamina-
tion, which leads to the selective formation of electronically unbiased
imines/ketones via directed [2+2] alkyne/Ti=NR cycloaddition. This
work will provide a basis for the development of other, selective Ti-cat-
alyzed reactions that can exploit transient dative interactions, expanding
directed Ti catalysis beyond classical alkoxide directing groups.
rected yield). Yields are reported with respect to 2a
.
Example Synthesis and Isolation of Multisubstituted Pyrroles via Heter-
ocoupling Reactions (Table 2, Condition B).
Experimental Section
Example for (5-(benzyloxy)pent-1-yn-1-yl)trimethylsilane (1g):
In a glovebox, to a 7 mL vial was added PhNNPh (41.0 mg, 0.225
mmol, 0.5 eq.), [(py)2Cl2TiNPh]2 (18.4 mg, 0.025 mmol, 0.055
1g
eq.), (5-(benzyloxy)pent-1-yn-1-yl)trimethylsilane ( ) (246 mg,
2a
0.1 mmol, 2.2 eq.), phenylpropyne ( ) (58.0 mg, 0.5 mmol, 1.1
eq.), and 2.5 mL PhCF3. The reaction was then sealed with a Tef-
General Considerations.
All air- and moisture-sensitive compounds were manipulated
in a glovebox under a nitrogen atmosphere. The solvent, PhCF3,
was predried in a Pure Process Technology Solvent System and
passed through activated basic alumina before being used. All high-
boiling liquid reagents were freeze pump-thawed three times,
brought into the glovebox, diluted in hexanes or diethyl ether,
passed through activated basic alumina, pumped dry in vacuo and
lon screw cap and heated at 115 °C outside of the glovebox in an
oil bath for 3 hours. The reaction was diluted by 2 mL ethyl acetate,
quenched by 2 mL 2M HCl in methanol for 1 hour, washed with
DI water, dried over Na2SO4 and concentrated prior to the purifi-
cation. The product 4g was isolated by silica gel chromatography
using 2% EA/Hex eluent to give a colorless oil (166 mg, 87% yield).
checked by 1H NMR in CDCl3 to ensure the dryness.
55
[(py)2TiCl2(NPh)]2 ,
phenyl)ethynyl)trimethylsilane
(THF)3TiI2(NPh)8,
1a),
((2-methoxy-
2-((trimethylsi-
(
lyl)ethynyl)pyridine (1p)8, trimethyl(thiophen-2-ylethynyl)silane
1u)8, 1-methoxy-2-(prop-1-yn-1-yl)benzene (1v)8, and (E)-1,2-
Yields are reported with respect to 2a
.
(
bis(4-bromophenyl)diazene5 were prepared according to reported
procedure. 1-Phenyl-1-propyne (2a) and 3-hexyne (2b) were pur-
chased from Sigma-Aldrich. Azobenzene was purchased from TCI
Chemicals and purified by dissolving it in hexanes and washing
with water. The organic layer was collected, dried over Na2SO4,
and the solvent was removed in vacuo.
1
Example No-D H NMR Determination of Pyrrole Regioisomeric Ra-
tios (Table 2, Condition A).
Example for ((2-methoxyphenyl)ethynyl)trimethylsilane (1a): In
a glovebox, to an NMR tube was added PhNNPh (8.2 mg, 0.045
mmol, 0.5 eq.), (THF)3I2TiNPh (6.1 mg, 0.01 mmol, 0.11 eq.),
((2-methoxyphenyl)ethynyl)trimethylsilane (1a) (20.4 mg, 0.1
mmol, 1.1 eq.), phenylpropyne (2a) (11.6 mg, 0.1 mmol, 1.1 eq.),
triphenylmethane (4.9 mg, 0.02 mmol, 0.22 eq.) as the internal
standard, and 0.5 mL PhCF3. The NMR tube was sealed and
brought out of the glovebox, and a t = 0 h No-D 1H NMR spectrum
was taken. The NMR tube was heated at 60 °C in an oil bath for 2
h. The NMR tube was then cooled to ambient temperature, and a
t = 2 h No-D 1H NMR spectrum was taken. Yields are reported with
13
1
1
1H, C, H-13C and 1H-15N HMBC, NOESY, and No-D H
NMR spectra were collected on Bruker Avance III HD NanoBay
400 MHz, Bruker Avance III HD 500 MHz, or Varian Inova 500
MHz spectrometers. High-resolution mass spectra were collected
on Agilent 7200 GC/QTOF-MS, Bruker BioTOF II ESI/TOF-
MS, or AB-Sciex 4800 MALDI/TOF-MS. Chemical shifts are re-
1
ported with references of residual protio-solvent impurity: H (s,
7.16 ppm for C6D5H; s, 7.27 for ppm CHCl3), 13C (t, 128.39 ppm
for C6D6; t, 77.23 ppm for CDCl3). No-D NMR spectrum were ref-
erenced to the proton signal of the internal standard triphenylme-
thane (Ph3CH, ppm = 5.0) at a delay time = 30 seconds and acqui-
sition time = 5 seconds.
respect to 2a
.
1
Example No-D H NMR Determination of Pyrrole Regioisomeric Ra-
tios (Table 2, Condition B).
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ACS Catalysis
Page 6 of 9
Example for (5-(benzyloxy)pent-1-yn-1-yl)trimethylsilane (1g):
Supporting Information
1
2
3
4
5
6
7
8
In a glovebox, to an NMR tube was added PhNNPh (8.2 mg, 0.045
mmol, 0.5 eq.), [(py)2Cl2TiNPh]2 (6.1 mg, 0.005 mmol, 0.055
eq.), (5-(benzyloxy)pent-1-yn-1-yl)trimethylsilane (1g) (49.2 mg,
0.2 mmol, 2.2 eq.), phenylpropyne (2a) (11.6 mg, 0.1 mmol, 1.1
eq.), triphenylmethane (4.9 mg, 0.02 mmol, 0.22 eq.) as the inter-
nal standard, and 0.5 mL PhCF3. The NMR tube was sealed and
brought out of the glovebox, and a t = 0 h No-D 1H NMR spectrum
was taken. The NMR tube was heated at 115 °C in an oil bath for 3
h. The NMR tube was then cooled to ambient temperature, and a
t = 3 h No-D 1H NMR spectrum was taken. Yields are reported with
Full experimental procedures, characterization data and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
*itonks@umn.edu
ORCID
Hsin-Chun Chiu: 0000-0002-9766-1133
Xin Yi See: 0000-0002-5523-0255
Ian A. Tonks: 0000-0001-8451-8875
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60
respect to 2a
.
Synthesis of 5-(5-bromo-2-((2,3-difluorobenzyl)oxy)phenyl)-1-(4-
bromophenyl)-2-methyl-3-phenyl-1H-pyrrole (5y).
Notes
Reaction of 1y with 2a to form 3y. In a glovebox, to a 20 mL vial
was added 283 mg 1y (1 eq., 1 mmol), 116 mg 2a (1 eq., 1 mmol),
166 mg (E)-1,2-bis(4-bromophenyl)diazene (0.5 eq., 0.5 mmol),
15 mg (THF)3I2TiNPh (2.5 %, 0.025 mmol)and 5 mL PhCF3. The
reaction was then sealed with a Teflon screw cap and heated in the
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by the National Institutes of Health
(1R35GM119457), and the Alfred P. Sloan Foundation (I.A.T. is a 2017
Sloan Fellow). Equipment for the Chemistry Department NMR facility
was supported through a grant from the National Institutes of Health
(S10OD011952) with matching funds from the University of Minne-
sota.
glovebox for 30 hours at 60 °C. After being cooled down to ambi-
ent temperature, the reaction was removed from the glovebox, 10
mL hexanes was added to the reaction, and the mixture was filtered
through a fine frit. The filtrate was concentrated in vacuo and
mixed with 10 mL 2M HCl in methanol. After 2-hour stirring, the
mixture was diluted by 20 mL DI water and extracted by hexanes
(15 mL x 3). The organic layer was washed with brine, dried by
MgSO4 and concentrated in vacuo to get a yellow solid, 3y, that was
carried on in the reaction as-is.
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mg, 22% overall yield with respect to 1y). H NMR (400 MHz,
C6D6): δ 7.62-7.60 (m, 2H), 7.35 (t, 3JHH = 7.8 Hz, 2H), 7.24 (dd,
3JHH = 7.5 Hz, 4JHH = 1.7 Hz, 1H), 7.18-7.15 (m, 1H), 6.97-6.93 (m,
2H), 6.90 (td, 3JHH = 7.9 Hz, 4JHH = 1.7 Hz, 1H), 6.77-6.71 (m ,3H),
6.65-6.58 (m, 3H), 6.54 (tdd, 3JHH = 7.9, 5.0 Hz, 4JHH = 1.4 Hz, 1H),
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=
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3
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selective pyrrole synthesis via directed TMS-alkyne insertion
tunable through directing group/catalyst matching
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Ph
R2
TMS
DG
cat. [Ti]
Ph
R2
N
+
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R2
TiIV
N
PhN=NPh
[2+2+1]
R3
DG = Lewis basic
dative directing group
DG
TMS
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R3
TMS
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via
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