Metal-ligand binding interactions in rhodium/palladium-catalyzed synthesis of dihydroquinolines

Article abstract of DOI:10.1021/jo502074s

A domino Rh- and Pd-catalyzed synthesis of dihydroquinolines is disclosed. Two metals and two ligands are placed in one reaction vessel along with the two reactive reagents to afford selective sequential coupling despite the potential for side reactions.

Full text of DOI:10.1021/jo502074s

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Article
Metal-Ligand Binding Interactions in Rhodium /
Palladium-Catalyzed Synthesis of Dihydroquinolines
Lei Zhang, Jane Panteleev, and Mark Lautens
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502074s • Publication Date (Web): 22 Oct 2014
Downloaded from http://pubs.acs.org on October 27, 2014
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MetalꢀLigand Binding Interactions in Rhodium /PalladiumꢀCatalyzed Synthesis of Dihydroquinolines
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Lei Zhang, Jane Panteleev, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St George St. Toronto, Ontario, Canada,
M5S 3H6
mlautens@chem.utoronto.ca
ABSTRACT: A domino Rh and Pdꢀcatalyzed synthesis of dihydroquinolines is disclosed. Two metals and two ligands are placed
in one reaction vessel along with the two reactive reagents to afford selective sequential coupling despite the potential for side
reactions. In this report, we describe mechanistic
investigations attempting to discern the catalystꢀ
ligand interactions occurring in this domino reaction.
Through these studies, the reactivity and relative
catalyst ligand loadings were successfully tuned to efficiently access the heterocyclic products.
Introduction
Metalꢀcatalyzed reactions play a central role in the synthesis of natural products, materials and bioactive substances. The
established approach is to conduct reactions one step at a time in sequence with a work up after each step and subsequent
purification. We sought to develop a domino reaction sequence that can occur in one vessel containing more than one metal
1,2
catalyst. The implications of this approach include reduction of time, waste, and adverse environmental impact. These advantages
may be useful in rapidly preparing structurally diverse compounds for biological screening or in the synthesis of a specific target on
2ꢀ6
larger scale. Although the use of two metals in various modes of catalysis (e.g. cooperative catalysis) has already yielded
powerful reactions, issues of incompatibility of reagents and the added issues of ligand effects on multiple catalytic cycles have not
been explored from a mechanistic perspective. Consequently, many examples of multiꢀmetal domino catalysis employ one ligand or
6
aꢀi
ligandꢀless conditions. As ligands are integral in controlling regioꢀ, stereoꢀ and enantioselectivity in metalꢀcatalyzed reactions,
their exclusion imposes significant limitations on reaction discovery and scope. Therefore, the development of multiꢀmetalꢀligand
domino catalysis may enable a broad range of useful transformations in a more practical way. The use of multiple ligands in multiꢀ
metal catalysis can facilitate optimization, improve reaction efficiency, and allow systematic ligand screening to fineꢀtune
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reactivity. Perhaps due to the complex nature of catalystꢀligand interactions in multiꢀcatalytic systems, the reports on multiꢀmetal
6kꢀp
and multiꢀligand systems have either simple metalꢀligand interactions or no analysis of metalꢀligand interactions was reported.
Exploring the dynamics and relative reactivity of multipleꢀmetalꢀligand interactions may unlock the full potential of multiꢀmetal
domino catalysis.
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Following our recent report on an efficient synthesis of dihydroquinolines employing two different metals and two different
ligands, we examined the nature of the metalꢀligand interactions in the system in more detail. The reaction involves a domino Rhꢀ
catalyzed addition of arylboronic acids to alkynes followed by a Pdꢀcatalyzed CꢀN cross coupling (Scheme 1). These studies have
shown 1) the effect of metalꢀligand exchange in catalysis, 2) the development of improved conditions based on a deeper
understanding of ligand effects in multiꢀmetal domino catalysis, and 3) an application in the synthesis of heterocycles, such as
dihydroquinolines and chromenes. We observed that among the various metalꢀligand species in the reaction vessel, the correct
combinations of the metalꢀligand complexes would catalyze two out of three possible reactions. We demonstrated that one of the
two metals selectively binds one of the ligands while the other metal binds both. However, due to the superior reactivity of one of
two metalꢀligand species, a successful domino sequence is observed.
Scheme 1. Proposed domino catalytic sequence
Results and Discussion
We initiated our studies with the optimization of the Rhꢀcatalyzed hydroarylation step (Table 1). The Rhꢀcatalyzed addition of
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aryl boronic acids to alkynes and alkenes was first disclosed by Miyaura and Hayashi. We were able to address issues of
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regioselectivity and reactivity of this formal hydroarylation reaction with directing groups such as pyridines and sulfones. While
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Marinelli and coworkers have previously demonstrated regioselective Rhꢀcatalyzed hydroarylation of aryl propargylamines,
achieving reactivity with a halogen substituent ortho to the alkyne proved to be challenging. For example, initial studies with 2ꢀ
bromoaryl alkynes did not give the desired reactivity and significant decomposition was observed. However, the less reactive 2ꢀ
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chloroaryl substrate 1a underwent hydroarylation with good conversion. While conducting an extensive ligand, solvent, and base
screening, we looked for conditions in the hydroarylation step that would not interfere with conditions suitable for the subsequent
CꢀN coupling. Employing [Rh(cod)OH] , BINAP (L1), PhB(OH) , and K CO , we observed favorable reactivity in either toluene
2
2
2
3
or dioxane. Screening of ligands L1 to L6 (Figure 1, Table 1, entries 4ꢀ8) demonstrated BINAP L1 as the ligand of choice for the
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hydroarylation. Although good regioselectivity was achieved, the yields were still moderate, and we explored the use of additives to
increase the yield. There are a number of studies on Rhꢀcatalyzed 1,4ꢀconjuage additions that utilized additives such as methanol,
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which significantly enhanced the yield and enantioselectivity and we found addition of methanol was very beneficial to the
hydroarylation. A notable increase in yield was observed and the regioselectivity of the hydroarylation was significantly enhanced
as no arylation α to the arene was seen (>25:1 vs. 10:1, Table 1, entries 10ꢀ12).
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Figure 1. Ligands screened for hydroarylation and CꢀN/O cross coupling
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Table 1. Optimization of the Rhꢀcatalyzed hydroarylation
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conv
NMR yield
conv
NMR yield
b
c
b
c
entry Ligand
solvent
EtOH
additive
entry ligand
solvent additive
(
%)
(%) (2a:4a)
(%)
(%) (2a:4a)
1
L3
100
Trace
7
L4
Diox
H
2
2
O
O
0
(
95%)
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L1
L1
L1
L5
L6
THF
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
100
100
100
77
40 (11:1)
45 (>25:1)
44 (10:1)
50 (>25:1)
8
9
L2
L1
L1
L1
L1
Diox
Diox
Diox
Diox
Diox
H
0
PhMe
100
100
100
100
44 (10:1)
f
g
Diox
10
MeOH
MeOH
MeOH
65 (>25:1)
h
Diox
Diox
11
77 (>25:1)
i
0
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69 (19:1)
a
[
Rh(cod)OH] with ligand were mixed in 1 mL dioxane for 15 min and then added to a vial containing 1a (0.2 mmol),
2
o
b
PhB(OH) , K CO and 0.1mL of additive. The mixture was stirred at 70 C for 16 h. 5.2 mol% for bidentate ligands, 10.4 mol%
2
2
3
c
d
e
for monodentate ligands. 10:1 solvent:additive. conv = conversion. Yield of 2a. Yield and regioselectivity were determined by
1
f
g
H NMR spectroscopy with 1,3,5ꢀtrimethoxybenzene as an internal standard introduced into the crude mixture. Diox = dioxane.
h
i
Reaction conducted at 60 °C. Isolated yield. Reaction conducted at 80 °C.
We explored the hydroarylation to evaluate its scope (Table 2) and found the reaction tolerated various substitution on the
arylboronic acid, including electron rich (entry 7), electron poor (entry 5), and heteroarylboronic acids (entries 8, 9). Deactivated
propargyl amines were tolerated. The unprotected amine did not participate well in the reaction. Substrates bearing the sulfonamide
group gave the highest yields. Alcohols also exhibited good reactivity (entries 10, 11).
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a
Table 2. Scope of Rhꢀcatalyzed hydroarylation
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a
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See supporting information for reaction procedures. Reactions conducted on 0.2 mmol scale. Reaction conducted at 60 C.
The adduct 2a following the hydroarylation was shown to undergo a Pdꢀcatalyzed intramolecular amidation (Table 3) to access
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dihydroquinolines of biological interest. While the aryl chloride was tolerated in the hydroarylation step, its inherently low
13,14
reactivity became a liability in the amidation step. Although intermolecular amination of aryl chlorides have been reported,
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examples with deactivated amides such as sulfonamides were rare, and secondary sulfonamides even more uncommon. Among
these examples, the typical reaction used inorganic bases, polar aprotic solvents, and elevated temperatures, similar to that of the
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hydroarylation. To effectively promote the amidation, we screened a number of ligands (Figure 1) that were suitable for coupling
of aryl chlorides (Table 3). We noted that the ligand used in the hydroarylation reaction, BINAP (L1), was not capable of affecting
the amidation (entries 1,8). Using dioxane and carbonate bases, we were pleased to observe a smooth conversion of the
hydroarylated intermediates 2a and 2b into dihydroquinolines 3a and 3b using Pd(OAc) and XPhos (L8, dicyclohexylphosphinoꢀ
2
2
’,4’,6’ꢀtriisopropylbiphenyl, entries 4ꢀ6) as the catalyst system.
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Table 3. Optimization of the Pdꢀcatalyzed amidation
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Pd(OAc) and ligand were mixed in 1 mL dioxane for 15 min and transferred to a vial containing 2 (0.2 mmol), and Cs CO (91
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2
3
o
b
1
mg, 1.4 equiv). The mixture was stirred at 90 C for 3 h. Determined by H NMR spectroscopy using 1,3,5ꢀtrimethoxybenzene as
c
the internal standard. With 10:1 dioxane:MeOH.
Establishing a twoꢀstep process provided access to dihydroquinoline 3a and 3b with a favorable overall yield of 61 and 71%
respectively. We subsequently shifted our focus to determining the viability of a domino process, which would further increase the
efficiency of this transformation. For consistency in the reaction protocol, we prepared the ligandꢀmetal solutions separately and
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added them to the reactants prior to heating. Performing the reaction without premixing the catalystꢀligand mixtures can achieve
the desired transformation, but with ca. 5% diminished yield. The domino transformation proceeded smoothly in a comparable
yield to the twoꢀstep reaction sequence (69 vs 71%, Scheme 2).
a
Scheme 2. Domino rhodium and palladium catalysis
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See Table 6 for domino reaction conditions.
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Although this reaction was operationally simple, the selective formation of the desired dihydroquinoline product was rather
fortuitous, since a number of problems could occur under the reaction conditions. For example, in the presence of two metals and
two ligands, a scrambling of metalꢀligand complexes and the formation of inactive or less active catalystꢀligand combinations are
possible. Another concern is that the presence of arylboronic acids, arylhalides, and palladium in the domino reaction could lead to
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an undesired SuzukiꢀMiyaura transformation (Scheme 3). Consequently, a timeꢀresolved and controlled reaction sequence was
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k
clearly present in this domino process. Since Jeong’s report, the development of a domino reaction with a rhodiumꢀpalladium
multiꢀligand system catalyzing mutually exclusive transformations has largely remained unexplored.
Scheme 3. Timeꢀresolved domino sequence and competitive reaction pathways
3
1
We probed the metalꢀligand interactions of a domino process by P NMR. In solution, we observed complexation of rhodium
with BINAP. However, to our surprise, [Rh(cod)OH] did not bind with XPhos, even with extended heating (Figure 2, entry
2
18,19
1
,2).
As a result, by adding BINAP to a solution of [Rh(cod)OH] and XPhos, we observed selective binding of [Rh(cod)OH]
2 2
to BINAP (entry 4). This unanticipated specificity had implications in realizing a number of tandem/domino reactions, including
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m,p
enantioselective variants that we have recently reported (Scheme 4).
We also attempted to investigate the multiꢀligand multiꢀ
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catalyst mixture with Rh/BINAP and Pd/XPhos directly via P NMR. However, the mixture decomposed over time or with
heating, posing difficulties in deducing the catalytic species present in the complex mixutre.
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XPhos
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+ XPhos, then
R)ꢀBINAP, 50 °C, 2 h
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(
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[Rh((R)ꢀBINAP)OH]
2
(R)ꢀBINAP
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[Rh(cod)OH]2
(R)ꢀBINAP, 50 °C, 1 h
+
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+ XPhos, 50 °C, 1 h
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entry
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Figure 2. P NMR spectra of Rh and ligand mixtures in benzene.
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Scheme 4. Ligandꢀspecific binding of [Rh(cod)OH] to BINAP
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For the rhodiumꢀcatalyzed step, we also carried out several control experiments, and the outcomes corroborated with
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our P NMR studies (Table 4). In the hydroarylation reaction, [Rh(BINAP)] was the agent responsible for catalysis (entry
2
). BINAP was essential as no hydroarylation occurred in reactions with [Rh(cod)OH] on its own or with added XPhos
2
(
entries 1, 3). Pd(OAc) was not an effective catalyst for the hydroarylation (entry 4). In fact, if only palladium and XPhos
2
were present with a mixture of the alkyne 1b and phenylboronic acid, SuzukiꢀMiyaura cross coupling was observed in
high yield (entry 5). Since the hydroarylation reaction occurred at 70 °C while the CꢀN cross coupling was sluggish at that
temperature, the rate difference provided the “timeꢀresolution” that was crucial to the success of the domino process.
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Table 4. Control Reactions for Domino Catalysis
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(2)
(2)
L8 (4)
76
a
b
1
See Table 6 for reaction procedures. Yields determined by H NMR spectroscopy using 1,3,5ꢀtrimethoxybenzene as
c
d
internal standard. Decomposition was observed. >25:1 regioselectivity
Subsequently, we tested the impact of added Pd(OAc) and XPhos on the efficiency of the hydroarylation step (Figure
2
3). The Rhꢀcatalyzed addition gave 70% conversion in 30 min at 70 °C (entry 1). The addition of XPhos had no effect,
further supporting that this ligand has minimal interaction with rhodium. However, adding Pd(OAc) to the reaction
2
caused a significant decrease in conversion (entry 3). It appeared that palladium may competitively bind BINAP, thus
stripping it from rhodium and diminishing the catalytic efficiency. Consequently, the addition of both Pd(OAc) and
2
XPhos to the reaction largely negated the competitive phosphine binding effect of added Pd(OAc) . As a result, high
2
conversion was restored for the Rhꢀcatalyzed hydroarylation (entry 4). At 5 mol% Pd(OAc) and 10 mol% XPhos loading
2
(
equivalent Rh:Pd loading), traces of the Suzuki cross coupling 5b and domino products 3b appeared. As the loading of
the palladium and XPhos increased, the amount of Suzuki coupling products 5b became significant (entry 5). From the
observations of reaction behavior it appeared that by fine tuning the catalytic components, a domino reaction was feasible.
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entry
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1
Figure 3. Effect of Pd and XPhos as additives in the hydroarylation step. Yields determined by H NMR spectroscopy
using 1,3,5ꢀtrimethoxybenzene as an internal standard.
With these initial studies in hand, we examined the Pdꢀcatalyzed amidation step and the influence of additives. Even in
the presence of a boronic acid, full conversion of 2b to the amidation product 3b was observed without the formation of
the SuzukiꢀMiyaura coupling product 6b (Scheme 5). The intramolecular cyclization outꢀcompeted the intermolecular
cross coupling.
Scheme 5. Competition reaction of amidation and SuzukiꢀMiyaura cross coupling
Driven by the control in selectivity observed during the amidation step in the presence of boronic acids, we proceeded to
probe the catalystꢀligand interactions between palladium, XPhos, and BINAP. In the Pdꢀcatalyzed amidation step, we
observed that BINAP attenuated the reaction (Figure 4). As the loading of BINAP increased from 4 mol% (2:1 L:Pd) to 8
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mol%, the reaction became so slow that no conversion was observed (entries 3, 4). The preferential binding of BINAP
with palladium diminished the amount of the active [Pd(XPhos)] species in the reaction medium. However, even with
20
premixing Pd(OAc) and BINAP to form the [Pd(BINAP)OAc ] complex prior to the addition of XPhos, we still
2
2
31
observed reactivity despite lowered conversion of 2b to the amidation product 3b (entries 5, 6). Using P NMR to
0
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investigate the ligand exchange at the premixing stage (Scheme 6, eq 1), we observed that Pd(OAc) preferentially binded
2
BINAP, a bidentate ligand, over XPhos, a bulky monodentate ligand, at room temperature (see supporting information).
While BINAP could displace XPhos on [Pd(II)(XPhos)] species, we did not observe the reverse process. However, the
preferential PdꢀBINAP association was not necessarily static under the reaction conditions. In addition, although Pd(II)
20
oxidation of BINAP to generate Pd(0) and BINAP(O) is a known process and could offer an explanation for the
observations made in Figure 4 (entries 5, 6), this was not a necessary mechanism responsible for ligandꢀexchange. For
instance, premixing [Rh(cod)OH] with XPhos and Pd(OAc) with BINAP could still lead to a successful domino reaction.
2
2
21
Switching the palladium source to PdꢀBINAPꢀGIII, a [Pd(0)ꢀBINAP] precursor developed by the Buchwald group, and
adding XPhos gave full conversion to the amidation product 3b (Scheme 6, eq 2). Buchwald and coworkers observed
22
exchange between RuPhos L9 and BrettPhos L10 on palladium so we were intrigued by the possibility of a weak
catalystꢀligand exchange occurring under our reaction conditions to generate sufficient amounts of the active [Pd(XPhos)]
species to catalyze the amidation step.
a
a
entry
1
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Figure 4. Effect of BINAP and ligand exchange on the amidation reaction. Pd(OAc) and XPhos were premixed for 30
2
31
min to fully form the ligandꢀbound species (observed via P NMR). BINAP was subsequently added and the mixture
a
stirred for an additional 30 min. The catalystꢀligand mixture was then subjected to the reaction. Pd(OAc) and BINAP
2
31
were premixed for 30 min to form [Pd(BINAP)(OAc) ] ( P NMR) followed by addition of XPhos and stirring for
2
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additional 30 min prior to subjecting to the reaction.
Scheme 6. BINAPꢀXPhos interactions with Pd in the amidation step
Ultimately the inhibitory effects of excess BINAP overwhelmed the weak PdꢀXPhos interactions in the Pdꢀcatalyzed
amidation step and significantly hindered conversion. However, the addition of [Rh(cod)OH] along with BINAP (Figure
2
5
, entry 4) ameliorated the inhibitory properties of BINAP, similar to the beneficial effect of adding both Pd(OAc) and
2
XPhos in the hydroarylation step. This result suggested that rhodium can competitively and selectively bind BINAP. The
active sequestration of BINAP by rhodium liberated palladium from the inactive [Pd(BINAP)] species and increased the
amount of the [Pd(XPhos)] complex. However, the loading of rhodium and BINAP relative to palladium and XPhos is
also important. When it was increased to 10 mol% (5:1 Rh:Pd), the amount of BINAP available to complex onto
palladium increased as well, leading to inhibition (entry 5).
Pd(OAc)2 (2 mol %)
XPhos (4 mol %)
2b
3b
K2CO3 (2.2 equiv), Dioxane
MeOH, 90 °C, 20 h
Additives: [Rh(cod)OH] , BINAP (L1)
2
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entry
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Figure 5. Influence of [Rh(cod)OH] and BINAP in the amidation reaction
2
With a better understanding of metalꢀligand interactions, we studied the effect of relative equivalents of the catalysts in
the domino reaction. With an equivalent loading of the two catalysts, the domino product 3b was formed in 50% yield
with full consumption of starting material 1b (Figure 6). It was apparent that lower loading of rhodium and BINAP
promoted SuzukiꢀMiyaura byproduct formation while high loading inhibited the amidation step. The optimal loading was
established at 2.5 mol% [Rh(cod)OH] (5 mol% Rh), 5.2 mol% BINAP, 2 mol% Pd(OAc) , and 4 mol% XPhos. Keeping
2
2
the metal catalyst loading at 5 mol% Rh and 2 mol% Pd, we varied the relative ligand loadings (Figure 7, 8). With
increased BINAP loadings the reaction stalled at the intermediate 2b. We attempted to outꢀcompete BINAP at 10 mol%
with increased loading of XPhos, but to no avail, observing even lower yields. The increased XPhos loading may result in
23
coordinative saturation of palladium, decreasing its catalytic activity.
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Figure 6. Determination of optimal catalyst ratios for the domino reaction
Figure 7. Effect of relative ligand loading on the formation of 2b in the domino reaction. See Table 5 for reaction
procedures.
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Figure 8. Effect of relative ligand loading on the formation of 3b in the domino reaction.
From the insights gained from these metalꢀligand interaction experiments, we propose that the two catalytic cycles
occurred independently and no cooperative interactions between the two catalytic cycles existed (Scheme 7). The cycles
commenced as the substrate 1 and arylboronic acid underwent rapid Rhꢀcatalyzed formal hydroarylation to yield 2. This
intermediate then entered the second catalytic cycle through a Pdꢀcatalyzed C–N coupling to yield the product 3. The
alternative undesired SuzukiꢀMiyaura crossꢀcoupling of 1b with the arylboronic acid could be observed. Additionally,
inhibition of the hydroarylation and C–N coupling by Pd(OAc) and BINAP respectively were observed. But with
2
optimized catalyst ratios, the alternative pathway and inhibition effects were suppressed.
Scheme 7. Proposed coexisting domino catalytic cycles
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With the synthetic conditions optimized, we investigated the scope of the domino process with respect to various
substitution patterns on the substrate and the arylboronic acid. We also investigated the nitrogen protecting group on the
substrate 1 (Table 5) amd observed the highest yields with mesyl and tosyl groups, though other sulfonyl groups were
tolerated.
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a
Table 5. Scope of nitrogen protecting groups
a
Stock catalyst solutions ([Rh(cod)OH] (0.005M) with BINAP (1.05 equiv to [Rh]) and Pd(OAc) (0.008M) with
2
2
o
XPhos (2 equiv to [Pd])), were mixed separately in dioxane at 50 C for 15 min. 0.5 mL of each solution was added to a
vial containing 1 (0.2 mmol), ArB(OH) (2 equiv), K CO (2.2 equiv) and 0.1mL MeOH in 1 mL of dioxane. The mixture
2
2
3
o
was stirred at 90 C for 16 to 20 h.
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Table 6. Scope of boronic acids in the domino reaction
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Using tosyl and mesyl protected substrates, we examined the scope of the arylboronic acid coupling partners (Table 6).
From a twoꢀstep perspective, the yields were good (39ꢀ78%). A variety of arylboronic acids were tolerated. Both electron
rich to poor boronic acids gave similar yields (entries 10ꢀ13). Excellent regioselectivity was observed with respect to the
alkyne for various boronic acids. Heteroaryl boronic acids also exhibited favorable reactivity. In particular, 3ꢀthiophenyl
boronic acid underwent the domino transformation with a 78% yield (entry 12).
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As we investigated the effects of substitution on the arene (Table 7), we found improved yields with deactivated
substrates (60ꢀ81%, entries 2ꢀ6). While electronꢀrich arenes were slightly lower yielding, the high regioselectivity of the
hydroarylation was retained. Various substitution patterns on the arene were well tolerated.
Table 7. Scope of Substitutions on Substrate
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a
b
See Table 5 for reaction conditions. Reaction conducted at 60 °C for 90 min and at 90 °C for the rest of the reaction
duration.
The hydroarylationꢀcross coupling strategy could also be applied to the synthesis of arylꢀ2Hꢀchromenes (Table 8).
Switching the palladium catalyst to [Pd(allyl)Cl] and the solvent to toluene resulted in an effective domino
2
hydroarylation/CꢀO cross coupling to afford the desired products with moderate yields.
Table 8. Synthesis of Chromenes
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The resulting dihydroquinoline products could be modified into the 3ꢀsubstituted quinoline via elimination of the
t
sulfonyl group in the presence of KO Bu at room temperature (Scheme 9, eq 1). The chromene 4h could be dihydroxylated
2
5
in high yield and ee (eq 2) and hydrogenation of the stilbene double bond can also be achieved under mild conditions.
Scheme 9. Post Modification of Domino Products
Conclusion
We have identified a synthesis of dihydroquinolines and chromenes via a twoꢀmetal, twoꢀligand domino process. This
work demonstrated that in spite of the potential complexity of metalꢀligand interactions, applying multiꢀmetalꢀligand
domino reactions could yield powerful transformations in one step with high efficiency. Through our studies on the
strength of the binding interactions, we gained valuable insight into the role of each individual component in this domino
reaction. Although inhibitory effects and side reactivity existed, modifications in the reaction conditions could counter
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these problems. Our work provided an example of two transitionꢀmetal complexes with different phosphine ligands
capable of association and dissociation whereby the active metalꢀligand complexes function independently to catalyze the
desired reaction pathway.
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Experimental Section
26
For general experimental methods see Supporting Information. Characterization data and experimental methods for 1j,
6l
28
1
b, 1l, 1n, 1o, 2b, 2i, 5b, 3lb, 3qb, 3rb, 4cꢀf, 4h, and 7 were reported previously.
Substrate syntheses
Nꢀ(3ꢀ(2ꢀchlorophenyl)propꢀ2ꢀynꢀ1ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide (1a)
A roundꢀbottom flask containing Pd(PPh ) Cl (71 mg, 1 mol%) and CuI (38 mg, 2 mol%) was purged with argon. N,Nꢀ
3
2
2
dimethylformamide (50 mL, 0.2M) and triethylamine (10.1 g, 13.9 mL, 100 mmol, 10 equiv) were added, followed by the
ꢀchloroꢀ1ꢀiodobenzene (2.62 g, 1.34 mL, 11 mmol, 1.1 equiv.) was added, followed by Nꢀ(propꢀ2ꢀ
2
ynyl)toluenesulfonamide (2.09 g, 10 mmol, 1 equiv) and the flask was stirred at r.t. for 16 hours. The reaction mixture was
diluted with EtOAc and partitioned with water. The organic phase was separated and washed with water 2x and brine,
dried over Na SO , filtered and concentrated under vacuum. Column chromatography (pentane:EtOAc 7:3) yielded the
2
4
1
titled compound as an offꢀwhite solid in 70% yield (2.24 g). H NMR (400 MHz, CDCl ): δ 7.81 (d, J = 8.3 Hz, 2H), 7.33
3
1
3
(d, J = 8.0 Hz, 1H), 7.30 – 7.18 (m, 3H), 7.15 (d, J = 4.2 Hz, 2H), 4.72 (s, 1H), 4.14 (d, J = 6.1 Hz, 2H), 2.32 (s, 3H).; C
NMR (100 MHz, CDCl ): δ 143.9, 136.9, 135.9, 133.5, 129.9, 129.7, 129.3, 127.6, 126.4, 122.2, 88.6, 81.7, 34.0, 21.6; IR
3
ꢀ1
(NaCl, neat): 3256, 2862, 1596, 1472, 1431, 1322, 1306, 1293, 1140, 1092, 1066, 963, 837, 819 cm ; M.p.: 134ꢀ136 °C;
+
+
HRMS (TOF, ESI ): calcd for C H ClNO S (M+H) : 320.0506; Found: 320.0499.
1
6
15
2
Nꢀ(3ꢀ(2ꢀChlorophenyl)propꢀ2ꢀynyl)methanesulfonamide (1b)
A roundꢀbottom flask containing Pd(PPh ) Cl (100 mg, 2 mol%) and CuI (60 mg, 4 mol%) was purged with argon.
3 2
2
Acetonitrile (30 mL, 0.2M) and triethylamine (30 mL, 0.2M) were added, followed by the 2ꢀchloroꢀ1ꢀiodobenzene (1.81 g,
0
.926 mL, 7.59 mmol, 1.1 equiv.) was added, followed by Nꢀ(propꢀ2ꢀynyl)methanesulfonamide 7 (918 mg, 6.9 mmol, 1
o
equiv) and the flask was stirred at 40 C for 4 hours when no starting material remained on TLC. The reaction crude was
filtered through a Celite plug and concentrated under vacuum. Column chromatography (pentane:EtOAc 7:3) yielded the
1
titled compound as an offꢀwhite solid in 75% yield (1.26 g). H NMR (400 MHz, CDCl ): δ 7.45 (dd, J = 7.5, 1.8 Hz,
3
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H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.29 (td, J = 7.8, 1.8 Hz, 1H), 7.23 (td, J = 7.5, 1.4 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H),
1
3
.27 (d, J = 6.2 Hz, 2H), 3.17 (s, 3H).; C NMR (100 MHz, CDCl ): δ136.1, 133. 130.1, 129.5, 126.8, 122.0, 89.3, 81.9,
3
41.8, 33.8.; IR (NaCl, neat): 3280, 3016, 2961, 2930, 2879, 1473, 1432, 1417, 1243, 1166, 1156, 1070, 1063, 1034, 996,
ꢀ
1
+
+
971, 827, 761, 739, 715, 667, 667, 589, 547, 522 cm ; M.p.: 65ꢀ67 °C; HRMS (TOF, EI ): calcd for C H ClNO S (M) :
10
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43.0121; Found: 243.0117.
tertꢀButyl 3ꢀ(2ꢀchlorophenyl)propꢀ2ꢀynylcarbamate (1d)
A roundꢀbottom flask containing Pd(PPh ) Cl (354 mg, 1 mol%), CuI (192 mg, 2 mol%), and a stirring bar was purged
3
2
2
with argon. Triethylamine (170 mL, 0.3M) was added. Following this, 2ꢀchloroꢀ1ꢀiodobenzene (12.0 g, 6.15mL, 50.5
mmol, 1.01 equiv) was added, followed by tertꢀbutyl propꢀ2ꢀynꢀ1ꢀylcarbamate (7.76 g, 50 mmol, 1 equiv), and the
reaction was allowed to stir at room temperature for 4 hours, at which point no starting material could be observed by
TLC. The reaction crude was filtered through a Celite plug and concentrated under vacuum. Column chromatography
1
(pentane:EtOAc 9:1) yielded the titled compound as a colorless solid in 95% yield (12.6 g). H NMR (400 MHz, CDCl ):
3
δ 7.42 (dd, J = 7.4, 1.8 Hz, 1H), 7.35 (dd, J = 7.9, 1.2 Hz, 1H), 7.21 (td, J = 7.7, 1.9 Hz, 1H), 7.16 (td, J = 7.5, 1.4 Hz,
13
1
1
H), 4.93 (s, 1H), 4.19 (d, J = 3.3 Hz, 2H), 1.45 (s, 9H); C NMR (101 MHz, CDCl ): δ 155.4, 136.0, 133.5, 129.4,
3
29.3, 126.5, 122.7, 90.9, 80.1, 79.9, 31.4, 28.4.; IR (NaCl, neat): 3343, 2979, 2933, 1712, 1679, 1505, 1475, 1368, 1274,
ꢀ
1
+
1249, 1168, 1064, 1049, 1033, 859, 755 cm ; M.p.: 58ꢀ60 °C; HRMS (TOF, DART+): calcd for C H ClNO (M+H) :
14
17
2
266.09478; Found: 266.09413.
General procedure A for protected propargyl amines:
A round bottom flask was charged with a stirring bar and tertꢀbutyl 3ꢀ(2ꢀchlorophenyl)propꢀ2ꢀynylcarbamate (11.93 g, 45
o
mmol, 1 equiv) and cooled to 0 C in an ice bath. A solution of HCl in EtOAc (3M, 30 mL) was added to this flask. The
(
aq)
reaction was allowed to stir at room temperature, until no starting material was observed by TLC (2h). The liquids were
removed uder reduced pressure, leaving an orange flaky solid (propꢀ2ꢀynꢀ1ꢀaminium chloride, 8.54g, 42.2 mmol), which
was used without further purification. In order to synthesize the protected propargyl amines, the propꢀ2ꢀynꢀ1ꢀaminium
chloride was treated with triethylamine and the appropriate electrophile in dichloromethane as described in each specific
case.
Nꢀ(3ꢀ(2ꢀChlorophenyl)propꢀ2ꢀynyl)benzenesulfonamide (1c)
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According to the general procedure A, propꢀ2ꢀynꢀ1ꢀaminium chloride (500mg, 2.474 mmol, 1 equiv) was placed into an
ovenꢀdried round bottom flask with a stirring bar; dichloromethane (10 mL, 0.25M) and triethylamine (550 mg, 0.757 mL,
o
5.4 mmol, 2.2 equiv) were added. The reaction was cooled to 0 C in an ice bath. Benzenesulfonyl chloride (480 mg, 0.35
mL, 2.7 mmol, 1.1 equiv) was added dropwise over ~3 minutes, and the reaction was allowed to warm to room
temperature. When the reaction was complete, as observed by TLC (<1h), the mixture was quenched with saturated
NH Cl , extracted with dichloromethane, washed with brine, and dried over MgSO . Afterwards, the solvent was
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4
(aq)
4
removed under reduced pressure, and the crude was purified using column chromatography (pentane:EtOAc 9:1 to 8:2)
1
yielding the title compound in 74% yield (560 mg) as a colorless solid. H NMR (400 MHz, CDCl ): δ 7.97 – 7.92 (m,
3
2
H), 7.56 – 7.44 (m, 3H), 7.36 – 7.30 (m, 1H), 7.22 (ddd, J = 8.0, 6.6, 2.5 Hz, 1H), 7.18 – 7.11 (m, 2H), 4.87 (t, J = 5.8
1
3
Hz, 1H), 4.16 (d, J = 6.1 Hz, 2H); C NMR (100 MHz, CDCl ): δ 139.9, 135.9, 133.5, 133.0, 129.8, 129.3, 129.3 (2),
3
127.5 (2), 126.4, 122.0, 88.4, 81.7, 34.0; IR (NaCl, neat): 3282, 3059, 2931, 2854, 1475, 1448, 1334, 1266, 1164, 1091,
ꢀ
1
+
1
072, 1032, 967, 947, 844, 730 cm ; M.p.: 84ꢀ85 °C; HRMS (TOF, EI+): calcd for C H ClNO S (M) : 305.0277;
15 12 2
Found: 305.0279.
Nꢀ(3ꢀ(2ꢀChlorophenyl)propꢀ2ꢀynyl)ꢀ4ꢀmethoxybenzenesulfonamide (1g)
According to the general procedure A, propꢀ2ꢀynꢀ1ꢀaminium chloride (303 mg, 1.5 mmol, 1 equiv) was placed into an
ovenꢀdried round bottom flask with a stirring bar; dichloromethane (5 mL, 0.3 M) and triethylamine (333.76 mg, 0.46 mL,
o
3.3 mmol, 2.2 equiv) were added. The reaction was cooled to 0 C in an ice bath. 4ꢀMethoxybenzeneꢀ1ꢀsulfonyl chloride
(341 mg, 1.1 equiv) in dichloromethane (1mL) was added dropwise over ~3 minutes, and the reaction was allowed to
warm to room temperature. When the reaction was complete, as observed by TLC (<1h), the mixture was quenched with
saturated NH Cl , extracted with dichloromethane, washed with brine, and dried over MgSO . Afterwards, the solvent
4
(aq)
4
was removed under reduced pressure, and the crude was purified using column chromatography (pentane:EtOAc 7:3 to
1
6
:4) yielding the title compound in 70% yield (352 mg) as a colorless solid. H NMR (400 MHz, CDCl ): δ 7.85 (d, J =
3
8.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.20 (ddd,J = 2.4, 6.8, 8.0 Hz, 1H), 7.17 – 7.08 (m, 2H), 6.89 (d, J = 8.9 Hz, 2H),
13
5.05 (t, J = 6.0 Hz, 1H), 4.11 (d, J = 6.1 Hz, 2H), 3.73 (s, 3H); C NMR (101 MHz, CDCl ):δ 163.1, 135.8, 133.5, 131.3,
3
1
1
29.7 (2), 129.6, 129.2, 126.4, 122.2, 114.3 (2), 88.8, 81.5, 55.6, 33.9; IR (NaCl, neat): 3268, 3094, 3023, 2981, 2854,
ꢀ
1
595, 1575, 1472, 1432, 1326, 1310, 1302, 1265, 1152 1073, 1022, 832, 763 cm ; M.p.: 105ꢀ107 °C; HRMS (TOF,
+
DART+): calcd for C H ClNO S (M+H) : 336.04612; Found: 336.04492.
1
6
15
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Nꢀ(3ꢀ(2ꢀChlorophenyl)propꢀ2ꢀynyl)ꢀ4ꢀnitrobenzenesulfonamide (1h)
According to the general procedure A, propꢀ2ꢀynꢀ1ꢀaminium chloride (303 mg, 1.5 mmol, 1 equiv) was placed into an
ovenꢀdried round bottom flask with a stirring bar; dichloromethane (5 mL, 0.3 M) and triethylamine (333.76 mg, 0.460
o
mL, 3.3 mmol, 2.2 equiv) were added. The reaction was cooled to 0 C in an ice bath. 4ꢀNitrobenzeneꢀ1ꢀsulfonyl chloride
0
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7
8
9
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8
9
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3
4
5
6
7
8
9
0
(366 mg, 1.1 equiv) in dichloromethane (1mL) was added dropwise over ~3 minutes, and the reaction was allowed to
warm to room temperature. When the reaction was complete, as observed by TLC (<1h), the mixture was quenched with
saturated NH Cl , extracted with dichloromethane, washed with brine, and dried over MgSO . Afterwards, the solvent
4
(aq)
4
was removed under reduced pressure, and the crude was purified using column chromatography (pentane:DCM:MeOH
1
4
7.5:47.5:5) yielding the title compound in 75% yield (385 mg) as a colorless solid. H NMR (400 MHz, CDCl ): δ 8.24
3
(dt, J = 2, 9.2 Hz, 2H), 8.12 (dt, J = 2, 8.8 Hz, 2H), 7.31 (dd, J = 8.1, 0.8 Hz, 1H), 7.22 (ddd, J = 2, 7.2, 8 Hz 1H), 7.13
13
(td, J = 7.4, 1.2 Hz, 1H), 7.09 (dd, J = 2, 7.6 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H); C NMR (100
MHz, CDCl ): δ 150.2, 146.0, 135.7, 133.2, 130.3, 129.5, 128.9 (2), 126.7, 124.4 (2), 121.5, 87.8, 82.4, 34.1; IR (NaCl,
3
ꢀ
1
neat): 3285, 3101, 3076, 1520, 1471, 1432, 1344, 1159, 1053, 857, 766, 736, 622 cm ; M.p.: 128ꢀ129 °C; HRMS (TOF,
+
DART+): calcd for C H ClN O S (M+NH ) : 368.04718; Found: 368.04750.
15 15
3
4
4
4ꢀ(2ꢀchlorophenyl)butꢀ3ꢀynꢀ1ꢀol (1k)
A roundꢀbottom flask containing Pd(PPh ) Cl (70 mg, 0.5 mol%), CuI (38 mg, 1 mol%), and a stirring bar was purged
3
2
2
with argon. Triethylamine (40 mL, 0.5M) was added. Following this, 2ꢀchloroꢀ1ꢀiodobenzene (5.25 g, 2.69mL, 22 mmol,
1.1 equiv) was added, followed by 3ꢀbutynꢀ1ꢀol (1.40 g, 1.51 mL, 20 mmol, 1 equiv), and the reaction mixture was
degassed with argon. The mixture was stirredat room temperature for 16 hours. The reaction crude was filtered through a
Celite plug and concentrated under vacuum. Column chromatography (pentane:EtOAc 9:1) yielded the titled compound
1
(
2.85 g) as yellow oil in 79% yield. H NMR (300 MHz, CDCl ): δ 7.49 – 7.41 (m, 1H), 7.41 – 7.35 (m, 1H), 7.28 – 7.14
3
13
(
m, 2H), 3.84 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.2 Hz, 2H); C NMR (75 MHz, CDCl ): δ 135.9, 133.3, 129.2, 129.1,
3
ꢀ
1
1
26.5, 123.2, 92.3, 79.6, 61.1, 24.1; IR (NaCl, CDCl ): 3335, 2943, 2888, 2234, 1476, 1431, 1065, 1045, 1034, 754 cm ;
3
HRMS (TOF, ESI+): calcd for C H ClO:181.0420, Found: 181.0419.
1
0
10
Nꢀ(3ꢀ(2ꢀChloroꢀ3ꢀfluorophenyl)propꢀ2ꢀynyl)methanesulfonamide (1l)
A roundꢀbottom flask containing Pd(PPh ) (58 mg, 5 mol%), CuI (19 mg, 10 mol%), 1ꢀbromoꢀ2ꢀchloroꢀ3ꢀfluorobonzene
3
4
(210 mg, 1 mmol) and Nꢀ(propꢀ2ꢀynyl)methanesulfonamide (160 mg, 1.2 mmol, 1.2 equiv.) was purged with argon.
o
Acetonitrile (5 mL, 0.2M) and diisopropylamine (5 mL, 0.2M) were added. The reaction was sealed and stirred at 90 C
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for 16 hours. The reaction crude was filtered through a Celite plug and concentrated under vacuum. Column
1
chromatography (hexane:EtOAc 9:1 to 8:2) yielded the titled compound as a colorless solid in 63% yield (165 mg). H
NMR (400MHz, CDCl ): δ 7.26 (d, J = 7.7 Hz, 1H), 7.20 (dt, J = 8.2, 5.1 Hz, 1H), 7.14 (dt, J = 8.6, 1.8 Hz, 1H), 5.11 (t,
3
13
J = 6.0 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.17 (s, 3H); C NMR (100MHz, CDCl ): δ 158.5 (d, J = 250 Hz), 129.0 (d, J
3
10
11
12
13
14
15
16
17
18
19
20
21
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=
3 Hz), 127.8 (d, J = 8 Hz), 123.4 (d, J = 18 Hz), 124.2 (s), 117.3 (d, J = 21 Hz), 90.5 (s), 80.8 (d, J = 4 Hz), 41.8 (s),
19
3
3.7 (s); F NMR (282 MHz, CDCl ): δ ꢀ112.99 (dd, J = 8.4, 5.2 Hz); IR (NaCl, neat): 3285, 1569, 1468, 1440, 1320,
3
ꢀ1
+
+
1
247, 1153, 1076, 1036, 787 cm ; M.p.: 100ꢀ103 °C; HRMS (TOF, ESI ): calcd for C H ClFNO S (M+H) : 262.0105;
10 10 2
found 262.0106.
Nꢀ(3ꢀ(3ꢀChloropyridinꢀ3ꢀyl)propꢀ2ꢀynyl)methanesulfonamide (1m)
A roundꢀbottom flask containing Pd(PPh ) (347 mg, 3 mol%) was purged with argon. Diisopropylamine (25 mL, 0.4M)
3 4
and 2ꢀbromoꢀ3ꢀchloropyridine (1.924 g, 10 mmol, 1 equiv) were added, followed by tertꢀbutyl propꢀ2ꢀynꢀ1ꢀylcarbamate
o
(1.86 g, 12 mmol, 1.2 equiv).The flask was stirred at 100 C for 16 hours. The reaction crude was filtered through a Celite
plug and concentrated under vacuum. Column chromatography (pentane:EtOAc 7:3) yielded tertꢀbutyl (3ꢀ(2ꢀ
chloropyridinꢀ3ꢀyl)propꢀ2ꢀynꢀ1ꢀyl)carbamate in 67% (1.79 g) yield as a brown solid. This material was then placed in a
o
round bottom flask, cooled to 0 C in an ice bath, and was treated with HCl in EtOAc (3M, 30 mL). The reaction was
(
aq)
monitored by TLC. Upon completion, the liquids were removed under vacuum to give a crystalline solid (3ꢀ(2ꢀ
chloropyridinꢀ3ꢀyl)propꢀ2ꢀynꢀ1ꢀaminium chloride). This material (500mg, 2.47 mmol, 1 equiv) was placed into a flameꢀ
dried round bottom flask. Dichloromethane (12 mL, 0.2M) and triethylamine (860mg, 1.15 mL, 6.18 mmol, 2.5 equiv)
o
were added. Upon cooling to 0 C in an ice bath, methanesulfonylchloride (340 mg, 227 ꢁl, 2.96 mmol, 1.2 equiv) was
added dropwise over ~3 minutes. The reaction was allowed to warm to room temperature and monitored by TLC. Upon
completion, the mixture was quenched with saturated NH Cl(aq), extracted with dichloromethane, washed with brine, and
4
dried over MgSO . Afterwards, the solvent was removed under reduced pressure, and the crude was purified using column
4
chromatography (pentane:EtOAc 1:1) yielding the title compound in 58% yield (351 mg, 39% overall) as a colorless solid.
1
H NMR (400 MHz, CDCl ): δ 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.23 (dd, J = 7.6, 4.9 Hz,
3
13
1
1
1
H), 4.86 (t,J = 5.3 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.16 (s, 3H); C NMR(101 MHz, CDCl ): δ 152.4, 149.1, 141.9,
3
ꢀ
1
22.1, 119.4, 91.9, 80.0, 41.9, 33.7; IR (NaCl, neat): 3269, 2918, 2850, 1395, 1318, 1152, 1092, 1070, 808 cm ; M.p.:
+
13ꢀ114 °C; HRMS (TOF, DART+): calcd for C H ClN O S (M+H) : 245.01515; Found: 245.01471.
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Nꢀ(3ꢀ(2ꢀChloroꢀ5ꢀfluorophenyl)propꢀ2ꢀynyl)methanesulfonamide (1n)
A roundꢀbottom flask containing Pd(PPh ) (58 mg, 5 mol%), CuI (19 mg, 10 mol%), 2ꢀbromoꢀ1ꢀchloroꢀ4ꢀfluorobonzene
3
4
(210 mg, 1 mmol) and Nꢀ(propꢀ2ꢀynyl)methanesulfonamide (160 mg, 1.2 mmol, 1.2 equiv.) was purged with argon.
o
Acetonitrile (5 mL, 0.2M) and diisopropylamine (5 mL, 0.2M) were added. The reaction was sealed and stirred at 90 C
for 16 hours. The reaction crude was filtered through a Celite plug and concentrated under vacuum. Column
0
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2
3
4
5
6
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8
9
0
1
2
3
4
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9
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0
1
chromatography (hexane:EtOAc 9:1 to 8:2) yielded the titled compound as a colorless solid in 56% yield (146 mg). H
NMR (300MHz, CDCl ): δ 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.16 (dd, J = 8.5, 3.0 Hz, 1H), 7.02 (ddd, J = 8.9, 7.9, 3.0 Hz,
3
13
1
H), 4.72 (s, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.16 (s, 3H); C NMR (75MHz, CDCl ): δ 161.0 (d, J = 248 Hz), 131.5 (d, J
3
=
4 Hz), 131.0 (d, J = 9 Hz), 123.6 (d, J = 10 Hz), 120.4 (d, J = 25 Hz), 117.8 (d, J = 23 Hz), 90.6 (s), 81.1 (d, J = 3 Hz),
19
4
1
2.0 (s), 33.8 (s); F NMR (282 MHz, CDCl ): δ ꢀ115.33 (td, J = 8.1, 5.1 Hz); IR (NaCl, neat): 3281, 1602, 1577, 1469,
3
ꢀ
1
+
405, 1320, 1154, 1120, 1000, 874, 817, 649 cm ; M.p.: 74ꢀ76 °C; HRMS (TOF, ESI ): calcd for C H ClFNO S
1
0
10
2
+
(M+H) , 262.0104; found 262.0105.
Nꢀ(3ꢀ(2ꢀChloroꢀ4ꢀ(trifluoromethyl)phenyl)propꢀ2ꢀynyl)methanesulfonamide (1o)
A roundꢀbottom flask containing Pd(PPh ) Cl (72 mg, 2 mol%) and CuI (44 mg, 4 mol%) was purged with argon.
3
2
2
Acetonitrile (25 mL, 0.2M) and triethylamine (25 mL, 0.2M) were added, followed by 2ꢀchloroꢀ1ꢀiodoꢀ4ꢀ
(trifluoromethyl)benzene (1.53 g, 5 mmol, 1 equiv.) was added, followed by Nꢀ(propꢀ2ꢀynyl)methanesulfonamide (732
o
mg, 5.5 mmol, 1.1 equiv.) and the flask was stirred at 40 C for 5 hours when no starting material remained on TLC. The
reaction crude was filtered through a Celite plug and concentrated under vacuum. Column chromatography
1
(hexane:EtOAc 9:1 to 8:2) yielded the titled compound as a pale yellow solid in 63% yield (0.98 g). H NMR (300MHz,
CDCl ): δ 7.68 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 4.75 (br s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.16 (s,
3
13
3
H); C NMR (75MHz, CDCl ): δ 136.6 (s), 133.9 (s), 131.8 (q, J = 34Hz), 126.5 (q, J = 4 Hz), 125.7 (s), 123.6 (q, J = 4
3
19
Hz), 123.0 (q, J = 273 Hz), 92.0 (s), 80.6 (s), 41.7 (s), 33.6 (s); F NMR (282 MHz, CDCl ): δ ꢀ63.5; IR (NaCl, neat):
3
ꢀ1
+
3
281, 1391, 1320, 1141, 1082, 834, 723 cm ; M.p.: 73ꢀ75 °C; HRMS (TOF, ESI ): calcd for C H ClF NO S: 312.0073;
11 10 3 2
Found: 312.0074.
Nꢀ(3ꢀChloroꢀ4ꢀ(3ꢀ(methylsulfonamido)propꢀ1ꢀynyl)phenyl)acetamide (1p)
A roundꢀbottom flask containing Pd(PPh ) Cl (58 mg, 5 mol%) and CuI (19 mg, 10 mol%) was purged with argon.
3
2
2
Acetonitrile (5 mL, 0.2M) and diisopropylamine (5 mL, 0.2M) were added, following this Nꢀ(4ꢀbromoꢀ3ꢀ
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chlorophenyl)acetamide (249 mg, 1 mmol, 1 equiv) was added, followed by Nꢀ(propꢀ2ꢀynyl)methanesulfonamide (173
o
mg, 1.3 equiv). The reaction was allowed to stir at 90 C for 16 hours. The reaction crude was filtered through a Celite
plug and concentrated under vacuum. Column chromatography (pentane:EtOAc 1:1) yielded the titled compound as a
1
colorlesssolid in 50% yield (150mg). H NMR (400 MHz, DMSO): δ 10.26 (bs, 1H), 7.89 (s, 1H), 7.66 (t, J = 5.3 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
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48
49
50
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56
57
58
59
60
1
3
7
.49 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.10 (d, J = 5.5 Hz, 2H), 3.03 (s, 3H), 2.06 (s, 3H); C NMR (101
MHz, DMSO): δ 169.0, 140.7, 134.8, 134.0, 118.7, 117.4, 115.5, 90.0, 80.0, 40.7, 32.6, 24.1; IR (neat): 3331, 3096, 3010,
ꢀ1
2
929, 2886, 1676, 1583, 1515, 1493, 1455, 1385, 1320, 1255, 1150, 1051, 1005, 964, 884, 843 cm ; M.p.: 171ꢀ172 °C;
+
HRMS (TOF, DART+): calcd for C H ClN O S (M+H) : 301.04137; Found: 301.04054.
1
2
14
2
3
Rhodiumꢀcatalyzed hydroarylation
General Procedure B for Rhꢀcatalyzed alkyne arylation: (Z)ꢀNꢀ(3ꢀ(2ꢀChlorophenyl)ꢀ2ꢀphenylallyl)
methanesulfonamide (2b)
[
Rh(cod)OH] (11.4 mg, 2.5 mol% (5 mol% [Rh])) and BINAP (32.4 mg, 5.2 mol%) were weighed into a 2ꢀdram vial,
2
which was fitted with a cap with a septum and purged with argon for 5 minutes. Dioxane (1 mL) was added to the vial and
o
the solution was allowed to stir for 15 minutes at 50 C (Note 1). Substrate 1b (244 mg, 1 mmol), phenylboronic acid
(
183mg, 1.5 mmol, 1.5 equiv), K CO (166 mg, 1.2 mmol, 1.2 equiv) were weighed into a 25mL roundꢀbottom flask,
2 3
which was fitted with a septum and purged with argon. 1,4ꢀDioxane (8 mL) and MeOH (0.8 mL) were added to the
o
reaction. The catalyst solution was added to this reaction flask via syringe. The reaction was heated to 50 C overnight
(16h), after which TLC showed complete consumption of phenylboronic acid. The reaction mixture was cooled to room
temperature, filtered through a plug of silica (washing with EtOAc), and the solvent was removed under vacuum. The
crude was purified using column chromatography (loading with toluene, pentane:EtOAc 8:2 to75:25) to yield a thick
yellow oil which slowly solidified upon standing (238 mg) in 74% yield (slightly higher yield (49.6 mg, 77%) was isolated
1
on 0.2 mmol scale). H NMR (400 MHz, CDCl ): δ 7.57 – 7.51 (m, 2H), 7.48 – 7.27 (m, 7H), 6.97 (s, 1H), 4.32 – 4.23 (m,
3
13
3
H), 2.72 (s, 3H); C NMR (100 MHz, CDCl ): δ 139.03, 138.39, 134.92, 134.02, 130.44, 129.86, 129.43, 129.38, 129.22
3
(
2C), 128.77, 127.09, 126.99 (2C), 42.49, 40.53; IR (NaCl, neat): 3282, 3058, 3023, 2963, 2932, 1496, 1471, 1445, 1428,
ꢀ
1
1409, 1318, 1264, 1153, 1067, 1052, 1034, 967, 883, 862, 836, 763, 699 cm ; M.p.: 77ꢀ78 °C; HRMS (TOF, DART+):
+
calcd for C H ClN O S (M+NH ) : 339.09340; Found: 339.09383.
16
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Note 1: Premixing [Rh(cod)OH] and BINAP was not crucial for the single step procedure and similar yields (70ꢀ77%)
2
were obtained if the catalyst and ligand were weighed as solids together with base and substrates.
(Z)ꢀNꢀ(3ꢀ(2ꢀchlorophenyl)ꢀ2ꢀphenylallyl)ꢀ4ꢀmethylbenzenesulfonamide (2a)
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The product was synthesized according to general procedure B, using [Rh(cod)OH] (2.3 mg, 2.5 mol%), BINAP (6.23
2
mg, 5 mol%), substrate 1a (64 mg, 0.2 mmol, 1 equiv), phenylboronic acid (49 mg, 0.4 mmol, 2 equiv) and K CO (31
2
3
mg, 0.22 mmol, 1.1 equiv). The crude product was purified by flash chromatography with 0ꢀ10% EtOAc/hexanes to
1
provide the title compound (58.1 mg) as an off white solid 73%. H NMR (400 MHz, CDCl ): δ 7.51 (d, J = 8.2 Hz, 2H),
3
7.31 (d, J = 7.7 Hz, 1H), 7.21 – 7.13 (m, 4H), 7.13 – 7.06 (m, 1H), 6.83 (s, 1H), 4.44 (s, 1H), 4.02 (d, J = 5.6 Hz, 2H), 2.38
13
(s, 3H); C NMR (101 MHz, CDCl ): δ 143.5, 138.7, 137.3, 136.2, 134.8, 134.0, 130.2, 129.7, 129.6, 129.2, 129.0, 128.9,
3
1
28.5, 127.3, 126.8, 126.7, 42.4, 21.7; IR (NaCl, CDCl ): 3266, 3057, 1660, 1599, 1471, 1445, 1404, 1327, 1163, 1094,
3
ꢀ
1
1
067, 1053, 887, 814, 760, 698, 667 cm ; M.p.: 127ꢀ129 °C; HRMS (TOF, ESI+): calc’d for C H NO SCl: 398.0976;
22 21 2
Found: 398.0985.
(Z)ꢀNꢀ(3ꢀ(2ꢀChlorophenyl)ꢀ2ꢀphenylallyl)benzenesulfonamide (2c)
The titled compound was synthesized using procedure B using [Rh(cod)OH] (2.3 mg, 2.5 mol%), BINAP (6.23 mg, 5
2
mol%), substrate 1c (61.2 mg, 0.2 mmol, 1 equiv.), phenylboronic acid (49 mg, 0.4 mmol, 2 equiv.) and K CO (31 mg,
2
3
0
.22 mmol, 1.1 equiv). The product was isolated through column chromatography (pentane:EtOAc 9:1) as a pale yellow
1
solid in 70% yield (48.6 mg). H NMR (400 MHz, CDCl ): δ 7.69 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J =
3
7
.7 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.34 – 7.26 (m, 5H), 7.26 – 7.10 (m, 3H), 6.89 (s, 1H), 4.49 (t, J = 5.2 Hz, 1H), 4.10
1
3
(
d, J = 5.6 Hz, 2H); C NMR (101 MHz, CDCl ): δ 139.2, 138.6, 137.2, 134.8, 134.0, 132.8, 130.2, 129.7, 129.3,
3
1
29.2(2), 129.0(2), 128.5, 127.3(2), 126.9, 126.7(2), 42.4; IR (NaCl, neat): 3260, 3061, 3023, 2917, 2849, 1471, 1447,
ꢀ
1
1321, 1166, 1095, 1066, 1049, 757, 721, 689 cm ; M.p.: 131ꢀ134 °C; HRMS (TOF, DART+): calcd for C H ClNO S
21
19
2
+
(M+H) : 384.08250; Found: 384.08289.
(Z)ꢀtertꢀButyl 3ꢀ(2ꢀchlorophenyl)ꢀ2ꢀphenylallylcarbamate (2d)
The titled compound was synthesized using procedure B using [Rh(cod)OH] (2.3 mg, 2.5 mol%), BINAP (6.23 mg, 5
2
mol%), substrate 1d (53.2 mg, 0.2 mmol, 1 equiv), phenylboronic acid (49 mg, 0.4 mmol, 2 equiv) and K CO (31 mg,
2
3
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9
0
.22 mmol, 1.1 equiv). The product was isolated through column chromatography (pentane:EtOAc 95:5) as a colorless
1
solid (33.7 mg) in 45% yield. H NMR (400 MHz, CDCl ): δ 7.56 (d, J = 7.4 Hz, 2H), 7.45 – 7.31 (m, 5H), 7.31 – 7.21
3
13
(m, 2H), 6.95 (s, 1H), 4.40 (s, 1H), 4.32 (d, J = 4.6 Hz, 2H), 1.37 (s, 9H); C NMR (101 MHz, CDCl ): δ 155.6, 139.6,
3
139.4, 135.3, 134.0, 130.5, 129.5, 128.8, 128.7, 128.1, 128.0, 126.9, 126.7, 79.4, 39.7, 28.3 (3); IR (NaCl, neat): 3335,
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ꢀ
1
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059, 3003, 2978, 2932, 1709, 1674, 1593, 1506, 1392, 1367, 1269, 1246, 1165, 1065, 1034, 860, 754 cm ; M.p.: 84ꢀ88
+
°
C; HRMS (TOF, DART+): calcd for C H ClNO (M+H) : 344.14173; Found: 344.14281.
2
0
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(Z)ꢀNꢀ(3ꢀ(2ꢀchlorophenyl)ꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)allyl)ꢀ4ꢀmethylbenzenesulfonamide (2e)
The product was synthesized according to general procedure B, using [Rh(cod)OH] (2.3 mg, 2.5 mol%), BINAP (6.23
2
mg, 5 mol%), substrate 1a (64 mg, 0.2 mmol, 1 equiv), (4ꢀ(trifluoromethyl)phenyl)boronic acid (76 mg, 0.4 mmol, 2
equiv) and K CO (31 mg, 0.22 mmol, 1.1 equiv). The crude was purified by flash chromatography with 0ꢀ10%
2
3
1
EtOAc/hexanes to provide the title compound (64.3 mg) as an off white solid 69%. H NMR (400 MHz, CDCl ): δ 7.53
3
(
d, J = 8.2 Hz, 3H), 7.43 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.28 – 7.13 (m, 5H), 6.93 (s, 1H), 4.61 (s, 1H), 4.07
13
(
d, J = 5.8 Hz, 2H), 2.43 (s, 3H); C NMR (75 MHz, CDCl ): δ 143.72 (s), 142.54 (s), 136.56 (s), 136.15 (s), 134.32 (s),
3
1
34.02 (s), 131.15 (s), 130.09 (s), 129.76 (s), 129.73 (s), 129.42 (s), 127.21 (s), 127.15 (s), 126.93 (s), 125.69 (q, J = 3.8
1
9
Hz), 42.37 (s), 21.60 (s); F NMR (377 MHz, CDCl ): δ 63.0 (s); IR (NaCl, CDCl ): 3264, 1616, 1435, 1323, 1161, 1123,
3
3
ꢀ
1
1072, 748 cm ; M.p.: 129ꢀ131°C; HRMS (TOF, ESI+): calc’d for C H NO F SCl: 466.0849; Found: 466.0835.
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2 3
(Z)ꢀNꢀ(3ꢀ(2ꢀchlorophenyl)ꢀ2ꢀ(pꢀtolyl)allyl)ꢀ4ꢀmethylbenzenesulfonamide (2f)
The product was synthesized according to general procedure B, using [Rh(cod)OH] (2.3 mg, 2.5 mol%), BINAP (6.23
2
mg, 5 mol%), substrate 1a (64 mg, 0.2 mmol, 1 equiv), (4ꢀ(methyl)phenyl)boronic acid (54 mg, 0.4 mmol, 2 equiv) and
K CO (31 mg, 0.22 mmol, 1.1 equiv). The crude was purified by flash chromatography with 0ꢀ10% EtOAc/hexanes to
2
3
1
provide the title compound (52.7 mg) as an off white solid 64%. H NMR (300 MHz, CDCl ): δ 7.57 (d, J = 8.3 Hz, 2H),
3
7.35 (d, J = 7.7 Hz, 1H), 7.26 – 7.08 (m, 9H), 6.85 (s, 1H), 4.39 (s, 1H), 4.05 (d, J = 5.6 Hz, 2H), 2.43 (s, 3H), 2.36 (s,
13
3
1
7
H); C NMR (101 MHz, CDCl ): δ 143.6, 138.5, 137.1, 136.2, 135.7, 134.9, 134.1, 130.2, 129.7, 129.7, 129.6, 129.0,
3
28.4, 127.4, 126.8, 126.6, 77.5, 77.2, 76.8, 42.4, 21.7, 21.3; IR (NaCl, CDCl ): 3244, 1435, 1316, 1165, 1096, 1065, 810,
3
ꢀ1
48, 706 cm ; M.p.: 122ꢀ125 °C; HRMS (TOF, ESI+): calc’d for C H NO SCl: 412.1132; Found: 412.1142.
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(Z)ꢀNꢀ(3ꢀ(2ꢀchlorophenyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)allyl)ꢀ4ꢀmethylbenzenesulfonamide (2g)
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