Reductive Alkylation of 2-Bromoazoles via Photoinduced Electron Transfer: A Versatile Strategy to Csp2-Csp3 Coupled Products

Article abstract of DOI:10.1021/acs.orglett.5b01711

Access to Csp²-Csp³-coupled products is a challenging goal at the forefront of catalysis. The photocatalytic reductive coupling of aryl bromides with unactivated alkenes is introduced as a convenient method that circumvents any need for synthesis of sp³-hybridized coupling partners. The reaction takes place via photoinduced electron transfer from a tertiary amine to an aryl bromide that fragments to provide an aryl radical and subsequently reacts with an alkene to form a C-C bond. Conveniently, the amine also serves as the final reductant. The method is operationally simple, functional group tolerant, and takes place with selectivities that will allow it to be used in the context of complex molecule synthesis.

Full text of DOI:10.1021/acs.orglett.5b01711

Letter
pubs.acs.org/OrgLett
Reductive Alkylation of 2‑Bromoazoles via Photoinduced Electron
2
3
Transfer: A Versatile Strategy to Csp −Csp Coupled Products
Amandeep Arora, Kip A. Teegardin, and Jimmie D. Weaver*
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078, United States
*
S Supporting Information
2
3
ABSTRACT: Access to Csp −Csp -coupled products is a
challenging goal at the forefront of catalysis. The photo-
catalytic reductive coupling of aryl bromides with unactivated
alkenes is introduced as a convenient method that circumvents
3
any need for synthesis of sp -hybridized coupling partners. The
reaction takes place via photoinduced electron transfer from a
tertiary amine to an aryl bromide that fragments to provide an
aryl radical and subsequently reacts with an alkene to form a C−C bond. Conveniently, the amine also serves as the final
reductant. The method is operationally simple, functional group tolerant, and takes place with selectivities that will allow it to be
used in the context of complex molecule synthesis.
1
1
zolesare a privileged scaffold thathave been investigated as a
often accomplished with the use of Bu SnH or by SmI2/
3
1
12
A
therapeutic for numerous diseases and 2-alkylazoles have
HMPA. Aside from toxicity issues associated with the organotin
and HMPA, the major drawback is the limitation inscope which is
due to fast over reduction of the desired aryl radical.
2
proven to be remarkable ROCK II inhibitors, yet there are
relatively few rapid syntheses. Consequently, there is a real need
to develop simple methods that allow the rapid construction of
complex 2-alkylazoles in order to facilitate thorough SAR studies.
The classic method for making 2-alkylazoles is via cyclo-
9
b
Consequently, almost all synthetically useful examples of aryl
radical addition to unactivated alkenes are intramolecular
9
,11c
cyclizations that can outcompete fast reduction.
3
dehydration and is still the most prominently used, but it is
Wespeculated thatavisible lightphotocatalyst could facilitate a
limitedtocarboxylicacidderivatives(eq1,SI-15). Cross-coupling
has the ability to expedite diversification, and recent efforts have4
provided several strategies. The first is to couple 2-bromoazoles
photoinduced electron transfer (PET) to the 2-bromobenzo-
13
thiazole, which would generate a 2-azoyl radical chemo- and
regioselectively that could engage unactivated alkenes to forge a
3
5
14
and preformed Csp -zincates (eq 2). Alternatively, alkyl halides
new C−C bond. Importantly, we hoped that the use of a
photocatalyst and an amine might prove to be sufficiently slow at
over reduction to allow the intermolecular C−C bond formation
take place. Furthermore, if successful, this strategy might be
extended to other reducible bromoarenes.
6
orhydrazones havealsobeenusedalongwith2H-benzothiazoles
(
eq 3).
Even more recently, oxidative methods have been used to
generate a radical, either by C−H abstraction or radical
decarboxylation (eq 4), and have proven quite selective for
13c
Previously, we showed that 2-chloroazoles could be used to
7
addition of the alkyl radical to the 2-position of an azole.
functionalize the α-C−H of tertiary aliphatic amines. However,
addition of electron-rich dihydropyran to 2-chlorothiazole (entry
3
3
However, Csp -halides, Csp -organometallics, or tosyl hydra-
zones represent a relatively small set of coupling partners that can
beusedasinputs forthecross-coupling. Tomaximizetheutilityof
a method, a large number of coupling partners should be readily
available. A strategy that has not been explored is the
photocatalytic generation of a 2-azoyl radical that could add
across an alkene and be followed by reduction of the incipient
1
, Table 1) yielded only reduced azole (1b) and carbinamine (1c)
as the majorproducts. However, use of the 2-bromoazole resulted
in a complete change in reactivity (entry 2) in which the
reductively coupled product was the major C−C product and the
carbinamine (1c) was not observed. On the basis of the work of
15
16
2
3
Bunnett and Rossi, who have shown that radical anions will
fragment a bromide faster than the corresponding chloride, it is
reasonable to think that the observed change in reactivity is due to
the nature of the reactive intermediates involved. Specifically, we
postulate that 2-chloroazoles undergo C−C formation via the
radical anion while 2-bromoazoles undergo C−C formation via
the radical. We next sought to increase the amount of C−C bond
forming product to reduction product (i.e., 1a + 1a′ vs 1b).
alkyl radical, amounting to a formal Csp −Csp cross-coupling
8
(
eq 5). Given the availability of alkenes, this transformation has
the immediate potential to significantly alter the types of motifs
thatcanbesyntheticallyaccessedbyrapidcross-coupling. Despite
this strategic advantage, general methods that allow intermo-
lecular reductive alkylation of aryl bromides have not been well
developed.
9
Radical addition to alkenes is well-known and represents a
promising strategy for the reductive alkylation of alkenes.
Pioneering work in this area has even shown that aryl bromides
can be converted to the aryl radical, and the conversion is most
Received: June 11, 2015
1
0
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01711
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions
reaction (entry 4 vs 5), with relative increases of 1a as the reaction
progressed. We suspected that this might be a result of acidic
species generated under the reaction conditions that could be
reducing the amount of free amine in solution and possibly
accelerating the formation of the desired product via a proton-
17
coupled electron transfer. Thus, we explored some acidic
17a
additives. Ultimately, we found a 1:1 mix of formic acid and
13a
tributylamine as the optimal additive.
We next explored the concentration of alkene. Consistent with
a process in which there is a competition for reduction and
alkylation of the azoyl radical, increased concentration of alkene
led to more alkylated products (1a + 1a′, entries 8−11). Further
concentrating the reaction also led to a slight improvement. In an
attempt to check the operational flexibility of the reaction, we
addedwater, whichresultedinonlyaslightdecrease ofthedesired
products. Finally, controls (entries 14 and 15) indicated that
photocatalyst, light, and amine are necessary components of the
1
8
reaction. Using 0.3 mol % of fac-tris(2-phenylpyridine)
Ir(ppy) ), a 1:1 mixture of amine and formic acid (3 equiv),
(
3
and 5 equiv of alkenes, we began to explore the scope of the
reaction.
Initially, we reacted a series of thiazoles with dihydropyran. We
obtained a 65% yield in a 6:1 regioisomeric ratio (rr) for simple 2-
bromothiazole (1a, Scheme 1). In most cases, substitution of the
thiazole increased the selectivity (1a vs 2a−7a). Products 5a and
6
a highlight an important feature of electron-addition-induced
a
1
b
fragmentation events that can be very selective and in these cases
display perfect chemoselectivity for the 2-bromo over the 4-
bromo and 5-bromo positions. The reaction works well for
benzothiazole (7a). However, the inclusion of a 5-chloro or 5,7-
difluoro slightly reduces the regioselectivity (8a, and 9a). In
contrast to thiazoles, we do not observe competitive reduction of
2-bromobenzimidazoles (10a), and consequently, yields are
higher, whereas under these conditions 2-bromooxazole (11a)
Conversion determined by H NMR. Product ratio determined by
GCMS.
Exchanging the ethyl of DIPEA for an isobutyl group (entry 3 vs
2
the expense of reaction time. Furthermore, we observed that the
product ratio was not constant throughout the course of the
) resulted in asignificant increase inthe desired product, albeit at
Scheme 1. Scope of the Reductive Alkylation
a
1
Yields correspond to isolated product. Regioisomeric ratio (rr) and diastereomeric ratio (dr) were determined by H NMR of the crude reaction
b
mixture after workup and on the isolated material. Isolated as an inseparable mixture (7:1) of product and oxidatively coupled product.
B
DOI: 10.1021/acs.orglett.5b01711
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Organic Letters
Letter
19
does not undergo reductive alkylation and highlights the impact
that the nature of the heterocycle has on the reaction.
Scheme 3. Thiazolation of Cholesterol
Next, we evaluated the nature of the alkene that could
participate in the reductive alkylation. In general, we found the
addition to be remarkably sensitive to the substitution pattern of
the alkene. Specifically, the addition typically occurred at the less
substituted carbon to provide the alkylated azoles in high
regioselectivity. The reaction works for monosubstituted- (13a),
1
,1-disubstituted (16a, 18a, 21a, 22a, 24, and 26a), 1,2-
disubstituted (5a−10a, 17a, 19a, 20a, 23a), trisubstituted (12a,
1
functional groups that likely would be sensitive to basic
organometallics work well in this method, including free alcohols
4a, 15a), and bridged alkenes (17a−23a). A number of
Scheme 4. Amine-Dependent Reduction Pathway Study
(
12a, 15a), acetates (16a), esters (23a), and enones (24a).
Believing that we were forming an azoyl radical, we were pleased
to see that weaker bonds, such as benzylic (26a), allylic (25a,
2
6a), as well as acetal C−Hs (13a), were well tolerated.
Furthermore, we saw no addition to the phenyl rings (14a,
6a), suggestingapreference forπ-electrons ofalkenesoverthose
of arenes.
Additionally, in more complex molecules containing multiple
2
alkenes we observed synthetically useful selectivities (24a−26a).
Interestingly, comparison of perillyl alcohol derivatives (25a,
2
6a) suggests that the presence of the free hydroxyl group can
reduction pathway since the reduction was likely directly
dependent on the amine concentration.
We tested this hypothesis using 2-bromothiazole, which is
prone to reduction (Scheme 4). Iterative amine addition
improved the product ratio (entry 2 vs 1) and supported our
hypothesis.
alter the inherent regioselectivity.
When these reaction conditions were applied to terpenoids
containingavinylcyclobutanemotif,weobservedclean, reductive
ring opening in good yields, high regioselectivity, and
diastereoselectivity. Addition of difluorobenzothiazole to α-
pineneprovided a68% yield ofan enantio- and diastereomerically
pure trisubstituted cyclohexene (eq 1, Scheme 2). The reaction of
We speculated that we could take advantage of the poor
solubility of tertiary amines with long alkyl chains (in MeCN) to
provide a convenient method for keeping a low concentration
over time. Thus, we evaluated the solubility of several amine
Scheme 2. Ring Opening of Vinylcyclobutanes
17a
derivatives and chose (iPr) NnOct, which was approximately
2
half as soluble as NBu . We were pleased to find that the use of the
3
less soluble amine did lead to an improved ratio of the desired
product (entry 3 vs 1). We also recognized that decreasing the
amine concentration might affect the rate of the photocatalytic
reaction. Thus, we rescreened photocatalysts using the less
1
7a
soluble amine.
We found that several more oxidizing
photocatalysts resulted in increased alkylated product ratios,
20
with Cat-1 providing the fastest reaction among these catalysts.
Using our modified conditions, we investigated more valuable
-bromo-4,6-difluorobenzothiazole as well as several of the
2
caryophyllene oxide afforded a single stereoisomeric product in
good yield (eq 2) with the epoxide functional group remaining
unchanged. The selectivity of the ring opening event suggests that
reductive azoylation of vinyl cyclobutanes may be a general and
convenient method for the formal allylic substitution with
concomitant ring enlargement.
The ability to easily and directly expand the carbon framework
of an alkene situated within a complex molecule presents an
exciting possibility as a late-stage functional group handle. Thus,
we examined the thiazolation of unprotected cholesterol which
gave a single stereoisomeric product (eq 3, Scheme 3).
poorer yielding substrates from Table 1 (Scheme 5). In all cases,
we observed increases in yield. We expect that these conditions
will be more ideal in cases where the azole is more precious and
reaction time is not.
Finally, we suspected that this type of reactivity should be
possible with other reducible bromoarenes. In our initial attempt,
we subjected electron-deficient bromopyrimidnes and benzenes
Scheme 5. Reduction-Minimizing Conditions
Next, we wanted to address a scenario in which the alkene was
more precious than the azole. Thus, we were forced to look at the
underlying problematic reduction that necessitated the use of an
excess of 2-bromothiazole. The amine is the stoichiometric
1
7a
reductant and is essential to the reaction.
1
7a
We speculated that it could also be facilitating undesired
reduction of the bromoazole. We hypothesized that lowering the
concentration of free amine could decrease the undesired
C
DOI: 10.1021/acs.orglett.5b01711
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
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*E-mail: jimmie.weaver@okstate.edu.
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The authors declare no competing financial interest.
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(
ACKNOWLEDGMENTS
■
J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.; Knowles, R. R. J. Am.
Chem. Soc. 2013, 135, 17735−17738. (c) Du, J.; Espelt, L. R.; Guzei, I. A.;
Yoon, T. P. Chem. Sci. 2011, 2, 2115−2119.
We thank Dr. Anuradha Singh of Oklahoma State University for
assistance in the measurement of amine solubilities. The research
results discussed herein were made possible in total or in part by
funding through the award for Project No. HR-14-072 from the
Oklahoma Center for the Advancement of Science and
Technology, by the NSF (CHE-1453891), and by OSU-startup
funds.
(18) In retrospect, 2-bromothiazole was an ideal substrate for
optimization since we have empirically observed it to have the greatest
tendency to undergo reduction of all the azoles that we have studied.
1
(19) The major product identified by GCMS and H NMR was the
corresponding carbinamine, 1-(benzo[d]oxazol-2-yl)-N,N-dibutylbu-
tan-1-amine.
(
20) Singh, A.; Teegardin, K.; Kelly, M.; Prasad, K. S.; Krishnan, S.;
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