Chemoselective Radical Dehalogenation and C-C Bond Formation on Aryl Halide Substrates Using Organic Photoredox Catalysts

Article abstract of DOI:10.1021/acs.joc.6b01034

Despite the number of methods available for dehalogenation and carbon-carbon bond formation using aryl halides, strategies that provide chemoselectivity for systems bearing multiple carbon-halogen bonds are still needed. Herein, we report the ability to tune the reduction potential of metal-free phenothiazine-based photoredox catalysts and demonstrate the application of these catalysts for chemoselective carbon-halogen bond activation to achieve C-C cross-coupling reactions as well as reductive dehalogenations. This procedure works both for conjugated polyhalides as well as unconjugated substrates. We further illustrate the usefulness of this protocol by intramolecular cyclization of a pyrrole substrate, an advanced building block for a family of natural products known to exhibit biological activity.

Full text of DOI:10.1021/acs.joc.6b01034

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Article
Chemoselective Radical Dehalogenation and C–C Bond Formation
on Aryl Halide Substrates Using Organic Photoredox Catalysts
Saemi Oh Poelma, G. Leslie Burnett, Emre H. Discekici, Kaila M. Mattson,
Nicolas J Treat, Yingdong Luo, Zachary M. Hudson, Shelby L Shankel,
Paul G Clark, John W. Kramer, Craig J. Hawker, and Javier Read de Alaniz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01034 • Publication Date (Web): 08 Jun 2016
Downloaded from http://pubs.acs.org on June 10, 2016
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Chemoselective Radical Dehalogenation and C–C Bond Formation on
Aryl Halide Substrates Using Organic Photoredox Catalysts
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Saemi O. Poelma, G. Leslie Burnett, Emre H. Discekici, Kaila M. Mattson, Nicolas J. Treat, Yingdong Luo, Zachary M.
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Hudson, Shelby L. Shankel, Paul G. Clark, John W. Kramer, Craig J. Hawker,* and Javier Read de Alaniz*
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Department of Chemistry and Biochemistry and Materials Department, Materials Research Laboratory, University of California, Santa
Barbara, California 93106, United States
§
The Dow Chemical Company, Midland, Michigan 48674, United States
Abstract: Despite the number of methods available for dehalogenation and carbon–carbon bond formation using aryl halides,
strategies that provide chemoselectivity for systems bearing multiple carbon–halogen bonds are still needed. Herein we report
the ability to tune the reduction potential of metalꢀfree phenothiazineꢀbased photoredox catalysts, and demonstrate the
application of these catalysts for chemoselective carbon–halogen bond activation to achieve C–C crossꢀcoupling reactions as
well as reductive dehalogenations. This procedure works both for conjugated polyhalides, as well as unconjugated substrates.
We further illustrate the usefulness of this protocol by intramolecular cyclization of a pyrrole substrate, an advanced building
block for a family of natural products known to exhibit biological activity.
Introduction
Reductive dehalogenation and carbon–carbon (C–C) crossꢀcoupling reactions with aryl halides are
widely utilized in the synthetic organic community as they facilitate the construction of a range of
valuable products. Standard methods in this field utilize metal catalysts, which present certain inherent
limitations such as high cost or toxicity (e.g. catalytic Pd, Ni, Rh or stoichiometric Bu SnH, SmI ), as
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,2,3
well as harsh and toxic reaction conditions (e.g. pressurized H , N H and HSiR as reductants).
To
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address these challenges, recent developments employing mild, photochemicalꢀbased procedures have
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,5
been reported with many photocatalysts being rare earth metalꢀbased. To avoid the use of expensive
metal catalysts there has been a concerted effort towards implementing organic photocatalysts, including
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perylenediimide (PDI) and eosin Y.
These photoredoxꢀbased reductions proceed via a carbon centered radical intermediate that is
subsequently trapped using an Hꢀatom source or, in many cases, a radical trapping species to form C–C
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bonds. This includes arylꢀaryl bond formations, as well as radical cyclizations and atom transfer radical
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,9,10,11,12
additions.
Such a versatile transformation warrants the development of photocatalytic systems
that can chemoselectively activate carbon–halogen bonds (C–X), giving potential for taking a single
synthetic derivative bearing multiple C–X bonds and synthesizing a large library of complex targets.
Currently, there are very few reports demonstrating the concept of chemoselective dehalogenations, and
13,14,15,16
these are limited to metalꢀbased nonꢀphotocatalyzed systems.
Our group recently reported the use of 10ꢀphenylphenothiazine (PTH, 1) for photomediated,
1
7,18,19
controlled radical polymerizations and radical dehalogenation of aryl and alkyl halides (Figure 1).
PTH was found to be a highly reducing organic photocatalyst (E * = ꢀ2.1 V vs. SCE), with the ability
1
/2
to access a variety of unactivated carbon–halogen bonds that were inaccessible with previous metalꢀfree
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systems. This initial work demonstrated that catalyst 1 can be used for dehalogenations, was tolerant of
oxygen and could be synthesized in a single step from commercially available materials. Herein we
apply this metalꢀfree photoredox strategy to the chemoselective activation of aryl groups bearing
multiple carbon–halogen bonds through catalyst design, specifically tuning the reduction potential of the
PTH scaffold. This approach can be applied to selective dehalogenation, as well as selective C–C bond
formation (Figure 2).
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O
O
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E
1/2* = -2.1 V
E
1/2* = -1.5 V
Figure 1. Structure and reduction potential of PTH (1) and trisꢀacetylꢀPTH (2).
R1
Catalyst 1
H-atom or Ar
R1
X1
Chemoselectivity via
Catalyst Design
X2
R1
Catalyst 2
H-atom or Ar
X
2
Figure 2. Representative scheme of a) chemoselective dehalogenation and b) chemoselective C–C bond formation on a
polyhalogenated substrate using an organic photoredox catalyst (X= halides, Ar= aryl group, R= Hꢀatom or aryl group).
Results and Discussion
In developing a catalyst to enable chemoselective reactivity, we hypothesized that incorporating
electronically deficient groups on the PTH scaffold could lower the excited state reduction potential of
catalyst 1. Thus, a trisꢀacetylꢀPTH catalyst (2) substituted with electron withdrawing groups on each aryl
ring para to the nitrogen was synthesized by subjecting 1 to a Friedel–Crafts acylation with AlCl in
3
acetic anhydride. This slight structural modification was found to have a significant influence on the
excited state reduction potential (E * = ꢀ1.5 V vs. SCE, see Figure 1) as compared to the originally
1
/2
employed photocatalyst. Furthermore, although visible light was not employed in this study, catalyst 2
was found to absorb well into the visible regime, giving the opportunity to use more mild sources of
irradiation while still reducing unactivated substrates.
After observing such a large difference in catalyst reduction potential, it was next sought to
understand whether or not these values translated into actual changes in reactivity. Thus, a representative
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aryl iodide (S1), bromide (3), and chloride (5) were chosen as test candidates for dehalogenations using
1
19
our previously optimized conditions, and reaction progress was monitored using H NMR. First,
iodobenzene was combined with tributylamine, formic acid, and catalyst 1 and within 1 h, near complete
conversion of the starting material to the dehalogenated product was observed (see SI Figure S1). In
contrast, when catalyst 2 was used under the same reaction conditions, little to no reaction was observed
after one hour. However, at 72 h both catalysts quantitatively reduced the substrate, which was an
encouraging initial result as it suggested differing rates of reactivity. Next, 3ꢀbromopyridine (3) was
examined, and a similar behavior occurred, with the rate of debromination using 1 again being
significantly faster (4 hrs ꢀ 78%) than when 2 was used (4 hrs ꢀ 14%) (Figure 3a). Again, quantitative
conversion of the substrate to the desired product could be achieved using both catalysts with prolonged
reaction times (see SI Figure S2). Next, a more challenging substrate bearing a C–Cl bond with an
activating ester group was examined (Figure 3b). In this case, 1 led to quantitative dechlorination within
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4 h, but the use of 2 was noticeably slower, reaching only 6% yield within the same time frame, and
still exhibiting low conversions after 72 h (21%) (see SI Figure S2). Importantly, these results are within
expectations for the relative reduction potentials of the catalysts, as iodides and bromides are known to
2
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have lower reduction potentials than chlorides. Encouraged by these results, it was hypothesized that
these different reaction rates would lead to selective dehalogenation on substrates with multiple carbon–
halogen bonds.
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Figure 3. Rate of dehalogenation of (a) 3ꢀbromopyridine (3) and (b) methyl 4ꢀchlorobenzoate (5) mediated by 1 and 2 for the
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first 4 h of reaction. H NMR yield determined using 1,2,4,5ꢀtetramethylbenzene as an internal standard.
To test chemoselective dehalogenation mediated by 2, we first examined the benzene derivative 7,
which is substituted with four different halogens: iodide, bromide, chloride and fluoride. The optimized
19
reaction conditions for reductive dehalogenation from the previously reported study were used. After 5
h of irradiation in the presence of 2, selective deiodination led to 8, which was obtained in 96% yield
with only 4% of deiodinated and debrominated product 9 being formed (Figure 4a). In contrast, when
catalyst 1 was used, no selectivity for the formation of 8 and 9 was observed (41% and 59% yield,
respectively) within the same 5 h time frame. However, after 48 h, the use of 1 as photocatalyst afforded
9
in 90% yield, demonstrating significant selectivity towards C–I and C–Br bonds over C–Cl and C–F
bonds (Figure 4b). Indeed, this initial study using a conjugated multiꢀhalogenated substrate gave
evidence that different bonds could be selectively activated by catalyst design.
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(
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I
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(5 mol %)
Cl
Cl
Cl
NBu , HCOOH
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+
+
F
F
380 nm light
F
Br
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I
MeCN, rt, 5 h
Br
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Br
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Br
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Figure 4. Chemoselective dehalogenation of 7 to its deiodinated product 8 and deiodinated and debrominated product 9 with
1
catalysts 1 and 2. H NMR yield determined using 1,2,4,5ꢀtetramethylbenzene as an internal standard.
We next examined the reduction of 2ꢀbromoꢀ6ꢀiodobenzonitrile (10) and envisioned that inclusion of
the electron withdrawing nitrile functionality would further activate the iodide and bromide, which
would help elucidate the tolerance of the iodideꢀselectivity for catalyst 2. As anticipated, utilizing 2 as a
photocatalyst led to the deiodinated product 11 in 97% yield with only 3% of 12 after 24 h (Figure 5a).
When the more reducing photocatalyst 1 was used, the fully reduced product 12 was afforded in 83%
yield after 24 h, and eventually increased to 96% yield after 48 h (Figure 5b). These experiments further
highlight that tuning the reduction potential of the PTH scaffold provides a strategy for chemoselective
dehalogenation.
Br
(a)
Br
2 (5 mol %)
NBu , HCOOH
CN
CN
CN
I
3
+
+
380 nm light
MeCN, rt, 24 h
1
0
11 (97%)
12 (3%)
Br
(b)
Br
1 (5 mol %)
NBu , HCOOH
CN
CN
CN
I
3
380 nm light
MeCN, rt, 48 h
10
11 (0%)
12 (96%)
Figure 5. Chemoselective dehalogenation of 10 to its deiodinated product 11 and deiodinated and debrominated product 12
1
with catalysts 1 and 2. H NMR yield determined using 1,2,4,5ꢀtetramethylbenzene as an internal standard.
To further investigate the potential of this approach, a substrate bearing activated C–I and C–Br
bonds on separate rings with a carbon spacer was prepared. In contrast to the previous substrate (10), we
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envisioned that this newly prepared bisꢀester (13) would allow for examination of the reduction of the
C–I bond without affecting the electronics of the other ring containing the C–Br bond (Figure 6). It was
found that with 2, deiodinated product 14 could be isolated in 84% yield after 48 h. With the use of 1,
both the iodide and bromide could be reduced to give 15 in 60% isolated yield in only 24 h.
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(5 mol %)
O
O
O
NBu , HCOOH
3
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O
O
O
O
O
O
380 nm light
380 nm light
DMSO, rt, 24 h
O
O
O
DMSO, rt, 48 h
I
1
4 (84%)
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15 (60%)
Figure 6. Selective dehalogenation of 13 with catalysts 1 and 2.
Having demonstrated successful chemoselective dehalogenation on substrates with multiple C–X
bonds with this methodology, we turned our attention to C–C bond forming reactions. Inspired by the
6
work of König and coworkers, we examined the C–C cross coupling of 4ꢀbromobenzonitrile (16) with
pyrrole in DMSO and found that the desired product 17 could be isolated in 56% yield (Figure 7a). The
key component in C–C bond formation was the use of a large excess of pyrrole to outꢀcompete the H
atom abstraction from tributylamine and facilitate trapping of the aryl radical. In addition, using a highly
polar solvent, DMSO, significantly aided the C–C bond formation, presumably due to its ability to
2
1
solvate the charged radical pairs of the catalyst and the substrate.
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pyrrole, NBu3
HN
Br
NC
380 nm light
DMSO, rt, 30 h
NC
1
6
17 (56%)
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I
O
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1 (5 mol %), NBu3
80 nm light
3
O
DMSO, rt, 84 h
N
O
O
MeO
MeO
R1
N
O
lamellarins
19 (59%)
Figure 7. C–C bond forming reactions of (a) 16 with pyrrole and (b) Intramolecular cyclization of 18 towards the core of the
lamellarins.
Following intermolecular arylꢀaryl cross coupling with pyrrole derivatives mediated by 1, we
explored the utility of the PTHꢀbased photoredox system for intramolecular cyclization. In particular, we
examined a system based on the lamellarins, which are polyaromatic marine alkaloids containing
condensed pentacyclic skeletons, and are known to show biological activity toward tumor cells (Figure
2
2,23
7
b).
First, an electron rich aryl iodide with a tethered pyrrole methyl ester (18) was prepared
2
4
according to a literature procedure. Using the same reaction conditions as for the coupling of 4ꢀ
bromobenzonitrile, only excluding the trapping agent, the lamellarin core (19) was isolated in 59%
yield.
Having successfully demonstrated C–C bond formation with PTH photocatalyst 2, we sought to
conduct C–C cross coupling reactions in a chemoselective manner. A substrate bearing C–I and C–Br
bonds with an activating nitrile group (10) was chosen as the model compound and subjected to the
same reaction conditions with an excess amount of pyrrole in the presence of catalyst 1 or 2 (Figure 8).
In the reaction with 1, diꢀsubstituted pyrrole 20 was obtained in 50% yield after 42 h. Of particular note,
when 2 was used as the photocatalyst, only the C–I bond was activated, leading to the formation of
monoꢀsubstituted pyrrole 21 in 55% yield. This result demonstrated that selective bond formation was
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achieved by the preferential reduction of the more highly accessible C–I bond over the corresponding
C–Br bond, producing an aryl radical, which in turn was trapped by pyrrole.
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NH
CN HN
CN
2 (5 mol %)
pyrrole, NBu
NH
CN
1
(5 mol %)
pyrrole, NBu3
I
Br
3
Br
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0
3
80 nm light
380 nm light
DMSO, rt, 50 h
DMSO, rt, 42 h
20 (50%)
10
21 (55%)
Figure 8. Selective C–C cross coupling reactions of a conjugated polyhalide with pyrrole.
In conclusion, we have developed a new metalꢀfree photoredox catalyst based on the PTH scaffold
to perform mild and efficient chemoselective dehalogenation and C–C bond forming reactions. We
observed that the less reducing catalyst, trisꢀacetylꢀPTH (2), can selectively activate C–I bonds whereas
the more reducing PTH catalyst (1) can activate both C–I and C–Br bonds. We believe that this protocol
will provide a simple, mild and efficient method for chemoselective dehalogenation and C–C coupling
reactions. Further investigation exploring a range of substrates to further elucidate the scope of this
methodology is currently underway.
Experimental Section
General Methods. Unless stated otherwise, reactions were conducted in flameꢀdried glassware under an
atmosphere of argon using reagentꢀgrade solvents. All commercially obtained reagents were used as
received. Reactions were performed at room temperature (rt, approximately 23 °C), unless stated
otherwise. LED strips (380 nm) were purchased from Elemental LED (see www.elementalled.com).
Reactions were placed next to the 380 nm source under vigorous stirring while cooling with compressed
2
air. The light intensity was measured to be 1.8 ꢁW/cm . Thinꢀlayer chromatography (TLC) was
conducted with E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by exposure to
UV light (254 nm) or stained with anisaldehyde or potassium permanganate. Flash column
1
chromatography was performed using normalꢀphase silica gel (60 Å, 230−240 mesh, Merck KGA). H
NMR spectra were recorded at 400, 500, or 600 MHz and are reported relative to deuterated solvent
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signals (7.26 ppm). Data for H NMR spectra are reported as follows: chemical shift (δ ppm),
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multiplicity, coupling constant (Hz), and integration. For quantitative H NMR to monitor yields, a 15ꢀ
second relaxation delay parameter was used with 1,2,4,5ꢀtetramethylbenzene as the internal standard.
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C NMR spectra were recorded at 100 or 125 MHz and are reported relative to deuterated solvent
1
3
signals (77.16 ppm). Data for C NMR spectra are reported as follows: shift (δ ppm). Highꢀresolution
mass spectra (HRMS) were obtained using a TOF mass spectrometer and infrared (IR) spectra were
obtained using a Fourier transform infrared spectrometer with an ATR accessory.
1,1'-(10-(4-Acetylphenyl)-10H-phenothiazine-3,7-diyl)bis(ethan-1-one) (2): To a 100 mL roundꢀ
bottom flask with stir bar was added CS (4.4 mL) and AlCl (871 mg, 6.5 mmol, 5.9 equiv). The
2
3
mixture was cooled to 0 ºC and a mixture of acetic anhydride (0.51 mL, 5.4 mmol, 4.9 equiv) and
phenyl phenothiazine (300 mg, 1.1 mmol, 1 equiv) in CS (2.7 mL) was slowly added dropwise via
2
dropping funnel, resulting in the immediate appearance of a dark purple color. The reaction was allowed
to warm slowly to room temperature, was stirred for 19 h, and poured over ice water (30 mL) resulting
in the immediate appearance of a yellow color. HCl (3M, 7 mL) was then added dropwise with stirring.
The mixture was washed with toluene (3 x 50 mL) and the combined organic layers washed successively
with deionized water, sat. aq. NaHCO , deionized water, and brine. The organic layer was dried over
3
MgSO , filtered, and concentrated to a yellow solid, which was purified by column chromatography
4
1
with toluene/EtOAc (17:3) to afford 2 (289 mg, 66% yield). mp 231–233 °C; H NMR (500 MHz,
CDCl ) δ 8.27 – 8.22 (m, 2H), 7.58 (d, J = 2.0 Hz, 2H), 7.51 – 7.47 (m, 2H), 7.41 (dd, J = 8.7, 2.1 Hz,
3
13
2
1
2
4
H), 6.09 (d, J = 8.6 Hz, 2H), 2.71 (s, 3H), 2.47 (s, 6H); C NMR (125 MHz, CDCl ) δ 196.9, 195.7,
3
46.2, 144.0, 137.7, 132.8, 131.5, 130.9, 128.2, 127.2, 119.9, 115.7, 26.9, 26.3; IR (ATR) 3104, 3056,
ꢀ1
+
993, 2922, 1664, 1568, 1475, 1237, 961, 822 cm ; HRMS (EI) m/z: [M] Calcd for C H NO S
2
4
19
3
01.1086; Found 401.1083.
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-Hydroxyethyl 4-iodobenzoate (S2): To a solution of ethylene glycol (2.0 mL, 35.863 mmol, 2.0
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9
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equiv), triethylamine (1.0 mL, 7.175 mmol, 2.0 equiv), and DMAP (0.0239 g, 0.196 mmol, 0.05 equiv)
in CH Cl (36 mL) at 0 °C was added 4ꢀiodobenzoyl chloride (0.9795 g, 3.676 mmol, 1.0 equiv). The
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solution was warmed to room temperature and stirred for 12 hours. The reaction was then quenched with
an ammonium chloride solution (1M, 20 mL). The aqueous layer was extracted with CH Cl (3 x 20
2
2
mL) and the combined organic layers were dried over MgSO , filtered, and then concentrated in vacuo.
4
The residue was purified by column chromatography with hexanes/EtOAc (gradient from 4:1 to 1:1) as
1
the eluant to afford S2 (0.83 g, 78%) as a colorless solid. mp 84–86 °C; H NMR (400 MHz, CDCl ) δ
3
13
7
.77 (dd, J = 20.0, 8.0 Hz, 4H), 4.46 – 4.42 (m, 2H), 3.96 – 3.92 (m, 2H), 2.21 (s, 1H); C NMR (100
MHz, CDCl ) δ 166.6, 137.9, 131.2, 129.4, 101.2, 66.9, 61.4; IR (ATR) 3497, 2958, 2916, 2873, 1695,
3
ꢀ1
+
1584, 1378, 1274, 1083 cm ; HRMS (EI) m/z: [M] Calcd for C H IO 291.9596; Found 291.9594.
9
9
3
2
-((4-Bromobenzoyl)oxy)ethyl 4-iodobenzoate (13): To a solution of S2 (0.8323 g, 2.850 mmol, 1.0
equiv), triethylamine (0.900 mL, 6.457 mmol, 2.3 equiv), and DMAP (10.0 mg, 0.082 mmol, 0.03
equiv) in CH Cl (12 mL) at 0 °C was added 4ꢀbromobenzoylchloride (1.110 g, 5.058 mmol, 1.8 equiv).
2
2
The solution was warmed to room temperature and stirred for 12 hours. The reaction was then quenched
with an ammonium chloride solution (1M, 30 mL). The aqueous layer was extracted with CH Cl (3 x
2
2
2
0 mL) and the combined organic layers were dried over MgSO , filtered, and then concentrated in
4
vacuo. The residue was purified by column chromatography with toluene/EtOAc (gradient from 100:0 to
1
99:1) as the eluant to afford 13 (1.35 g, 99%) as a colorless solid. mp 142–144 °C; H NMR (400 MHz,
CDCl ) δ 7.90 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz,
3
1
3
2
H), 4.65 (s, 4H); C NMR (100 MHz, CDCl ) δ 166.0, 165.8, 138.0, 132.0, 131.3, 131.2, 129.3, 128.7,
3
ꢀ1
1
28.5, 101.3, 63.0; IR (ATR) 3083, 3033, 2960, 1709, 1583, 1258, 1101, 1010 cm ; HRMS (EI) m/z:
+
[
M] Calcd for C H BrIO 473.8964; Found 473.8968.
16
12
4
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2
-(Benzoyloxy)ethyl 4-bromobenzoate (14): A vial equipped with a magnetic stir bar and fitted with a
teflon screw cap septum was charged with 13 (47.5 mg, 0.100 mmol, 1.0 equiv), trisꢀacetylꢀPTH (2.0
mg, 0.095 mmol, 0.05 equiv), formic acid (19 ꢁL, 0.504 mmol, 5.0 equiv), tributylamine (120 ꢁL, 0.504
mmol, 5.0 equiv), and DMSO (1 mL). The reaction mixture was sparged for 15 minutes with argon and
then vigorously stirred in front of 380 nm LEDs while cooling with compressed air to maintain ambient
temperature. After 48 hours, the reaction mixture was diluted with EtOAc (10 mL) and quenched with
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H O (30 mL). After the layers were separated, the aqueous layer was extracted with EtOAc (3 x 20 mL)
2
and the combined organic layers were dried over MgSO , filtered, and concentrated in vacuo. The
4
residue was purified by column chromatography with hexanes/EtOAc (gradient from 99:1 to 7:1) as the
1
eluant to afford 14 (29.2 mg, 84%) as a colorless solid. mp 41–44 °C; H NMR (500 MHz, CDCl ) δ
3
8.05 (d, J = 6.9 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.61 – 7.53 (m, 3H), 7.44 (t, J = 7.8 Hz, 2H), 4.66 (s,
13
4
H); C NMR (100 MHz, CDCl ) δ 166.5, 165.8, 133.3, 131.9, 131.3, 129.8, 128.8, 128.6, 128.54,
3
ꢀ1
1
28.46, 63.1, 62.7; IR (ATR) 3064, 2955, 2920, 1717, 1590, 1451, 1398, 1259, 1096 cm ; HRMS (EI)
+
m/z: [M] Calcd for C H BrO 347.9997; Found 347.9990.
16
13
4
Ethane-1,2-diyl dibenzoate (15): A vial equipped with a magnetic stir bar and fitted with a teflon screw
cap septum was charged with 13 (49.9 mg, 0.100 mmol, 1.0 equiv), PTH (1.4 mg, 0.005 mmol, 0.05
equiv), formic acid (19 ꢁL, 0.504 mmol, 5.0 equiv), tributylamine (120 ꢁL, 0.504 mmol, 5.0 equiv), and
DMSO (1 mL). The reaction mixture was sparged for 15 minutes with argon and then vigorously stirred
in front of 380 nm LEDs while cooling with compressed air to maintain ambient temperature. After 48
hours, the reaction mixture was diluted with EtOAc (10 mL) and quenched with H O (30 mL). After the
2
layers were separated, the aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined
organic layers were dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by
4
column chromatography with hexanes/EtOAc (gradient from 99:1 to 7:1) as the eluant to afford 15 (16.2
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mg, 60%) as a colorless solid. mp 64–66 °C; H NMR (400 MHz, CDCl ) δ 8.07 (d, J = 7.4 Hz, 4H),
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
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4
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5
5
5
6
1
3
7
.57 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.6 Hz, 4H), 4.67 (s, 4H); C NMR (100 MHz, CDCl ) δ 166.5,
3
ꢀ1
1
33.3, 129.9, 129.8, 128.6, 62.9; IR (ATR) 3064, 2959, 2914, 1710, 1602, 1451, 1265, 1113 cm ;
0
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+
HRMS (EI) m/z: [M] Calcd for C H O 270.0892; Found 270.0889.
1
6
14
4
4-(1H-Pyrrol-2-yl)benzonitrile (17): To a 1 dram vial was added a solution of 16 (18.2 mg, 0.100
mmol, 1.0 equiv), pyrrole (0.35 mL, 5.00 mmol, 50.0 equiv), 1 (1.4 mg, 0.005 mmol, 0.05 equiv), and
tributylamine (0.12 mL, 0.500 mmol, 5.0 equiv) in DMSO (1.0 mL). The solution was purged with
argon for 10 minutes. The vial was placed next to the 380 nm lights under vigorous stirring while
cooling with compressed air for 24 h. The reaction was then quenched by adding DI water and the crude
product was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine,
dried over MgSO , and filtered. The solvent was removed in vacuo and the product was purified by
4
column chromatography using hexane/EtOAc (99:1 to 70:30) to afford 17 (9.4 mg, 56% yield) as
2
6
1
yellowish crystals. mp 102–104 °C; H NMR (400 MHz, CDCl ) δ 8.62 (s, 1H), 7.63 (d, J = 8.4 Hz,
3
1
3
2
H), 7.54 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 6.67 (s, 1H), 6.35 (q, J = 2.7 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 136.8, 132.9, 130.2, 123.8, 121.1, 119.3, 111.1, 108.9; IR (ATR) 3358, 3103, 3058, 2996,
3
ꢀ1
+
2923, 2852, 2223, 1606, 1502, 1453, 1418, 1180, 1116, 839 cm ; HRMS (EI) m/z: [M] Calcd for
C H N 168.0687; Found 168.0682.
11
8
2
Methyl
1-(2-iodo-4,5-dimethoxyphenethyl)-1H-pyrrole-2-carboxylate
(18):
Methyl
2ꢀ
pyrrolecarboxylate (216 mg, 1.7 mmol, 1.0 equiv) and NaH (60% dispersion, 74 mg, 1.85 mmol, 1.1
equiv) were stirred in dry DMF (3.4 mL) in an iceꢀbath for 30 min. A solution of 2ꢀiodoꢀ4,5ꢀ
2
7
dimethoxyphenethyl 4ꢀmethylbenzenesulfonate (957 mg, 2.1 mmol, 1.2 equiv) in dry DMF (4.3 mL)
was added and the mixture was stirred for 20 h at room temperature. The DMF was then evaporated
under reduced pressure, and Et O was added. The organic solution was washed with 1M HCl, saturated
2
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NaHCO and brine, and dried and concentrated. The residue was purified by column chromatography
3
with hexanes/EtOAc (gradient from 95:5 to 90:10) to afford 18 (485 mg, 68%) as a white solid. mp 69–
1
7
1
1 °C; H NMR (600 MHz, CDCl ) δ 7.20 (s, 1H), 6.95 (dd, J = 3.9, 1.8 Hz, 1H), 6.56 (t, J = 2.2 Hz,
3
0
1
2
3
4
5
6
7
8
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0
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H), 6.36 (s, 1H), 6.02 (dd, J = 4.0, 2.5 Hz, 1H), 4.47 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.71
13
(s, 3H), 3.11 (t, J = 6.9 Hz, 2H); C NMR (100 MHz, CDCl ) δ 161.6, 149.2, 148.3, 133.5, 129.5,
3
1
21.4, 121.3, 118.6, 112.9, 107.9, 88.0, 56.2, 55.9, 51.2, 49.3, 42.2; IR (ATR) 3101, 2950, 2836, 1698,
ꢀ1
+
1
507, 1437, 1330, 1239, 1211, 1107 cm ; HRMS (EI) m/z: [M] Calcd for C H INO 415.0281;
16 18 4
Found 415.0285.
Methyl 8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (19): To a 2 dram vial
was added a solution of 18 (400 mg, 0.96 mmol, 1.0 equiv), 1 (13.3 mg, 0.05 mmol, 0.05 equiv) and
tributylamine (1.1 mL, 4.8 mmol, 5.0 equiv) in DMSO (4.8 mL). The solution was purged with argon
for 10 minutes. The vial was placed next to the 380 nm lights under vigorous stirring while cooling with
compressed air for 84 h. The reaction was then quenched by adding DI water and the crude product was
extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine and DI water,
dried over Na SO and filtered. The solvent was removed in vacuo and the product was purified by
2
4
column chromatography using hexane/EtOAc (gradient from 100:0 to 70:30) to afford 19 (163 mg, 59%
1
yield) as offꢀwhite crystals. mp 86–89 °C; H NMR (400 MHz, CDCl ) δ 7.05 (s, 1H), 7.00 (d, J = 4.1
3
Hz, 1H), 6.73 (s, 1H), 6.42 (d, J = 4.1 Hz, 1H), 4.60 (t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.83
1
3
(s, 3H), 3.01 (t, J = 6.8 Hz, 2H); C NMR (100 MHz, CDCl ) δ 161.9, 148.8, 148.3, 136.5, 124.7, 121.4,
3
1
21.1, 118.5, 111.0, 106.9, 103.5, 56.2, 56.1, 51.2, 42.4, 28.7; IR (ATR) 3000, 2954, 2933, 2850, 1694,
ꢀ1
+
1
611, 1429, 1243, 1130, 1007, 856, 759 cm ; HRMS (EI) m/z: [M] Calcd for C H NO 287.1158;
16 17 4
Found 287.1160.
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,6-Di(1H-pyrrol-2-yl)benzonitrile (20): To a 2 dram vial was added a solution of 10 (154 mg, 0.500
4
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6
7
8
9
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1
1
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mmol, 1.0 equiv), pyrrole (1.75 mL, 25.0 mmol, 50.0 equiv), 1 (6.9 mg, 0.025 mmol, 0.05 equiv), and
tributylamine (0.60 mL, 2.5 mmol, 5.0 equiv) in DMSO (2.5 mL). The solution was purged with argon
for 10 minutes. The vial was placed next to the 380 nm lights under vigorous stirring while cooling with
compressed air for 50 h. The reaction was then quenched by adding DI water and the crude product was
extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine and DI water,
dried over Na SO and filtered. The solvent was removed in vacuo and the product was purified by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
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8
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9
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8
9
0
2
4
column chromatography using hexane/EtOAc (gradient from 9:1 to 2:1) to afford 20 (59.0 mg, 50%
1
yield) as offꢀwhite solid. mp 190–193 °C; H NMR (500 MHz, CDCl ) δ 9.16 (s, 2H), 7.52 (dd, J = 8.6,
3
7.1 Hz, 1H), 7.44 (d, J = 0.5 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H), 6.99 (td, J = 2.8, 1.5 Hz, 2H), 6.81 (ddd,
1
3
J = 3.7, 2.7, 1.5 Hz, 2H), 6.36 (dt, J = 3.7, 2.6 Hz, 2H); C NMR (100 MHz, CDCl ) δ 137.6, 133.2,
3
1
28.4, 124.9, 121.2, 120.9, 111.0, 110.4, 101.5; IR (ATR) 3406, 3362, 3121, 2957, 2924, 2853, 2212,
ꢀ1
+
1579, 1468, 1416, 1113, 1088, 1036, 798, 739 cm ; HRMS (EI) m/z: [MꢀH] Calcd for C H N
3
15
10
2
32.0875; Found 232.0868.
2
-Bromo-6-(1H-pyrrol-2-yl)benzonitrile (21): To a 2 dram vial was added a solution of 10 (154 mg,
0.500 mmol, 1.0 equiv), pyrrole (1.75 mL, 25.0 mmol, 50.0 equiv), 2 (10.0 mg, 0.025 mmol, 0.05
equiv), and tributylamine (0.60 mL, 2.5 mmol, 5.0 equiv) in DMSO (2.5 mL). The solution was purged
with argon for 10 minutes. The vial was placed next to the 380 nm lights under vigorous stirring while
cooling with compressed air for 50 h. The reaction was then quenched by adding DI water and the crude
product was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine
and DI water, dried over Na SO and filtered. The solvent was removed in vacuo and the product was
2
4
purified by column chromatography using hexane/EtOAc (gradient from 9:1 to 2:1) to afford 21 (67.1
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1
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2
2
2
2
2
2
2
2
2
2
3
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5
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6
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mg, 55% yield) as offꢀwhite solid. mp 131–133 °C; H NMR (400 MHz, CDCl ) δ 9.29 (s, 1H), 7.59 (d,
3
J = 8.1 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.83 (s, 1H), 6.40 – 6.31
13
(
m, 1H); C NMR (100 MHz, CDCl ) δ 138.4, 133.8, 129.9, 127.32, 127.26, 125.6, 121.7, 118.7, 111.6,
3
0
1
2
3
4
5
6
7
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
1
10.7, 109.2; IR (ATR) 3388, 3072, 2918, 2852, 2226, 1586, 1558, 1543, 1460, 1125, 1042, 730 cm ;
+
HRMS (EI) m/z: [M] Calcd for C H N Br 245.9793; Found 245.9798.
1
1
7
2
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org
NMR conversions for S1, 3, and 5
Proposed mechanism for dehalogenation
NMR spectra of isolated products 2, S2, 13–15, 17–21
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: hawker@mrl.ucsb.edu
*
Eꢀmail: javier@chem.ucsb.edu
ACKNOWLEDGMENT
We thank the MRSEC program of the National Science Foundation (DMR 1121053) and The Dow
Chemical Company through the Dow Materials Institute at UCSB for financial support. NMR
instrumentation was supported by the NIH Shared Instrumentation Grant (SIG): 1S10OD012077ꢀ01A1.
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