Palladium-catalyzed α-arylation of sultams with aryl and heteroaryl iodides

Article abstract of DOI:10.1021/ol501389k

Palladium(0)-catalyzed conditions for the α-arylation of sultams with aryl and heteroaryl iodides have been developed. Arylation of 3-substituted 1,3-propanesultams gave rise to high yields and high diastereomeric ratios, leading to the thermodynamically

Full text of DOI:10.1021/ol501389k

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Arylation of Sultams with Aryl and Heteroaryl
Iodides
Olivier Rene,*,† Benjamin P. Fauber,† Sushant Malhotra,‡ and Herbert Yajima‡
́
†Discovery Chemistry and ‡Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080,
United States
S
* Supporting Information
ABSTRACT: Palladium(0)-catalyzed conditions for the α-
arylation of sultams with aryl and heteroaryl iodides have been
developed. Arylation of 3-substituted 1,3-propanesultams gave
rise to high yields and high diastereomeric ratios, leading to the
thermodynamically favored cis product. The arylation was
broadly applicable to various electron-rich and electron-poor
(hetero)aromatic iodides.
lectivity for C3-substituted 1,3,-propanesultams bearing a
n recent years, sultams (cyclic sulfonamides) have
Iincreasingly received significant attention due to their sterically demanding substituent.
biological activity. Although not found in natural products,1
several sultam-containing compounds have found medicinal
uses in diverse therapeutic areas, such as oncology,2 virology,3
immunology,4 treatment of neurological disorders,5 and
others.6 As a result, a proliferating number of synthetic routes
to access the sultam core have been reported.7 Despite the large
number of sultam ring-forming reactions, all of the reported
methods require the desired functionalities around the carbon
framework of the ring to be installed prior to the formation of
the sultam ring.
As part of our research program, we became interested in
establishing a method for late-stage incorporation of diverse
arenes and heteroarenes onto a preformed sultam ring that
would allow for rapid and divergent synthesis of C5-substituted
analogues. We envisioned that the α-arylation of the sultam
ring would be the most efficient transformation to accomplish
this process, as it would not require any prefunctionalization of
the C5 position of the sultam ring prior to the arylation step.
Although the α-arylation of carbonyl compounds is a well-
established transformation,8 the arylation of sulfonyl and
sulfoxide compounds is a more challenging process due to
the decreased acidity of the α-protons.9 Reports include the
Pd(0)-catalyzed arylation of methyl sulfoxides using a LiOt-Bu
base.9 There are also three-operation processes for the arylation
of unactivated sulfones10 and acyclic sulfonamides,11 wherein
deprotonation was first performed with a strong base, followed
by transmetalation with ZnCl2 prior to a Pd(0)-catalyzed
Negishi-type cross-coupling. However, these methods were less
applicable to the arylation of sultams, and as shown in Scheme
1, the reported three-operation process for the arylation of
acyclic sulfonamides did not prove suitable for the arylation of
their sultam counterpart.12 Herein, we report an operationally
simple one-step process for Pd(0)-catalyzed α-arylation of 1,3-
propane sultams that features the use of TMPZnCl·LiCl13 as
the base. Furthermore, our process displays good diastereose-
Initial reaction development and optimization on the Pd(0)-
catalyzed α-arylation of sultam 1 using 10 mol % Pd(dba)2, 10
mol % RuPhos, and iodobenzene in THF with various bases
revealed the superiority of TMPZnCl·LiCl. The base could be
used to activate the α-position in situ, obviating the need for a
preactivation step. Other bases such as LiHMDS, KHMDS,
NaOt-Bu, and TMPMgCl·LiCl14 were not competent for the
transformation and did not lead to formation of product. The
use of iodobenzene also proved to be the optimal electrophile.
With chlorobenzene (Table 1, entry 1) as the electrophile, the
reaction reached 39% completion in 4 h, while bromobenzene
(entry 2) gave 78% conversion. In the same amount of time,
complete formation of product was observed with iodobenzene
(entry 3).15
As shown in Table 1, the stoichiometry of the TMPZnCl·
LiCl base was also essential in achieving both high conversion
and diastereocontrol. For example, the use of only 1 equiv of
base (entry 4) resulted in an incomplete conversion and a low
diastereomeric ratio (dr) of 0.7:1 (cis:trans), only slightly
favoring the trans diastereomer. Conversely, the use of a large
excess (5 equiv) of base (entry 5) gave rise to a high dr of 10:1
(cis:trans), largely favoring the cis isomer, albeit in 77%
conversion. The optimal amount of base was found to be 2.5
equiv (entry 3), which resulted in complete conversion to the
cis sultam 2 in high dr. Additionally, subjecting a 1:12 mixture
of 2:3 to TMPZnCl·LiCl (2.5 equiv) in THF at 60 °C afforded
a 9:1 mixture of 2:3. Presumably, sultam 2 was the
thermodynamic product and the reaction selectivity was
determined by the relative energy difference between the two
diastereomers when an excess of base was used.
The use of other biaryl-type ligands did not provide notable
changes in the reaction outcome, as illustrated with X-Phos
Received: May 14, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Scheme 1. Previously Reported Three-Operation Arylation Process for Acyclic Sulfonamides Gave Low Yield with Sultam 1
Table 1. Optimization of Reaction Conditions
Table 2. Effect of the C3 Substituent on the
Diastereoselectivity of the α-Arylation
a
a
entry
Ph-X
solvent
ligand
Y
convn (%)
2:3
1
Ph-Cl
Ph-Br
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
X-Phos
JohnPhos
Xantphos
PPh3
2.5
2.5
2.5
1.0
5.0
2.5
2.5
2.5
2.5
2.5
39
78
98
88
77
98
93
46
65
98
9:1
9:1
2
3
4
9:1
a
Determined by unpurified 1H NMR analysis of the sultam C5 proton
0.7:1
10:1
9:1
5
6
7
9:1
substituent significantly contributes to the diastereomeric
outcome of the reaction, with the bulkier substituent giving
rise to the thermodynamically preferred cis product in high dr.16
Exploration of the scope of the aryl iodide coupling partner
was accomplished using commercially available N-(4-methox-
ybenzyl)-1,3-propanesultam 8, obviating the need for separat-
ing mixture of diastereomers and providing a suitable
chromophore on the starting material for ease of purification.
Illustrative examples of substituted arenes are shown in Table 3.
Iodobenzene (Table 3, entry 1) performed similarly well in this
system compared to the C3-substituted sultams and gave the
desired product 9 in 82% yield. Additionally, electron-
withdrawing substituents such as a m-cyano (entry 2) and p-
methyl ester (entry 3) were suitable coupling partners and gave
rise to the coupled products 10 and 11 in 41% and 52% yields,
respectively. Interestingly, the chloro functionality (entry 4)
was preserved under the reaction conditions, making it available
for further functionalization, and provided arylated sultam 12 in
50% yield. Moreover, the electron-rich dioxine-bearing aryl
iodide (entry 5) performed well and afforded product 13 in
87% yield. The more sterically hindered 1-iodonaphthalene
(entry 6) and 1-iodo-2-methoxybenzene (entry 7) electrophiles
gave rise to the corresponding arylated products 14 and 15 in
65% and 74% yields, respectively.
8
10:1
7:1
9
10
RuPhos
7:1
a
Determined by HPLC analysis.
(Table 1, entry 6) and JohnPhos (entry 7). Bidentate ligand
Xantphos (entry 8) and triphenylphosphine (entry 9) resulted
in significantly lower conversions. The use of toluene as a
solvent (entry 10) was also well tolerated with 98% conversion,
albeit with a slightly lower dr.
Having established optimized conditions for the α-arylation
of sultam 1, we evaluated the applicability of the transformation
with different C3 substituents on the sultam ring and the effect
of the substituent size on the diastereomeric ratio. As illustrated
in Table 2, the α-arylation reaction proceeded in high yield with
R = methyl (Table 2, entry 1) with an isolated yield of 85% for
product 6 and a 2.5:1 dr. The slightly more sterically
demanding isobutyl-containing sultam (entry 2) also proved
to be a suitable coupling partner and gave rise to the arylated
product 7 in 75% yield, with a slightly improved 3:1 dr in favor
of the cis product. Furthermore, the bulkier phenyl substituent
(entry 3) gave the arylated product 2 in 89% isolated yield and
9:1 dr. Overall, it appears that the steric demand of the C3
B
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Table 3. Scope of Substituted Aryl Iodides
Table 4. Scope of Heteroaryl Iodides
We were also pleased to observe that the method was
suitable for the α-arylation of our model sultam with a variety
of heterocyclic iodides, as illustrated in Table 4. For example, 4-
iodopyrimidine (Table 4, entry 1) coupled well and provided
the desired product 16 in 73% yield. Other azine heterocycles
such as 2-iodopyridine (entry 2) and 3-iodopyridine (entry 3)
afforded the arylated sultams 17 and 18, in yields of 46% and
26%, respectively. In addition, N-Boc-5-iodoindole, as well as 6-
iodo-2-methylbenzo[d]thiazole, were competent coupling
partners and provided the corresponding products 19 and 20
in moderate yield for the indole (entry 4) and low yield for the
benzothiazole (entry 5). 3-Iodothiophene was also a suitable
coupling partner and provided the arylated sultam 21 in 42%
yield (entry 6).
Some observed limitations to the reaction included the use of
certain heterocyclic iodides shown in Figure 1. Examples
included azole-type heterocycles 3-iodo-1-methyl-1H-indazole
and 4-iodo-1-methyl-1H-pyrazole, as well as 2-iodo-5-methyl-
thiophene, which all gave <10% conversion by HPLC. Some
azine-type heterocycles such as 2-iodopyrimidine or 4-chloro-6-
iodoquinazoline, which contained a highly activated chloride,
Figure 1. Unsuccessful heterocyclic iodides demonstrating the current
limitations of the sultam α-arylation method.
failed to provide the desired product in isolable quantities.
Pd(0)-catalyzed cross-couplings with these types of hetero-
cycles are typically considered to be challenging due to a
difficult oxidative insertion of Pd(0) or to the ligation of the
nitrogen-containing heterocycle onto palladium, which results
in the displacement of the desired phosphine ligands, reducing
the activity of the catalyst.17 We also found that formation of a
quaternary center by subjecting an α-substituted sultam to our
reported conditions did not proceed. However, this matter is
under further investigation.
In conclusion, we have developed general conditions for the
α-arylation of sultams. The process was operationally simple
and did not require preactivation of the sultam C−H bond
prior to cross-coupling. A broad variety of substituted aryl
C
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(9) Jia, T.; Bellomo, A.; Baina, K. E.; Dreher, S. D.; Walsh, P. J. J. Am.
Chem. Soc. 2013, 135, 3740.
(10) Zhou, G.; Ting, P. C.; Aslanian, R. G. Tetrahedron Lett. 2010,
iodides were compatible, such as electron-rich, electron-poor,
and sterically hindered (hetero)aromatic iodides. In the
presence of a C3 substituent on the sultam, moderate to high
diastereomeric ratios were obtained, which were dictated by the
steric hindrance of the substituent.
51, 939.
(11) Zhou, G.; Ting, P.; Aslanian, R.; Piwinski, J. J. Org. Lett. 2008,
10, 2517.
(12) Reference 11 reports arylation conditions using 1.2 mol %
catalyst loading. Under those conditions, arylation of sultam 1 gave
product in 4% yield. For a more accurate comparison, the same
reaction was repeated using 10 mol % catalyst loading, and an 18%
yield with no dr was observed. Additionally, the use of bromobenzene
under our conditions gave rise to arylated product in 67% isolated
yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization with spectral data for
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. For a
review on functionalized organometallic reagents, see: (b) Klatt, T.;
AUTHOR INFORMATION
■
Markiewicz, J. T.; Samann, C.; Knochel, P. J. Org. Chem. 2014, 79,
̈
Corresponding Author
4253.
(14) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
(15) We also observed that complete consumption of the starting
materials occurred with chlorobenzene and bromobenzene after a
reaction time of 16 h, with isolated yields of 49% and 67%,
respectively.
*E-mail: rene.olivier@gene.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) A-values were used to approximate the steric hindrance of the
C3 substituents in our system. Methyl A-value = 1.7; phenyl A-value =
3.0. See: (a) Hirsch, J. A. Topics in Stereochemistry; John Wiley & Sons,
Inc.: New York, 1967; p 199. (b) Jensen, F. R.; Bushweller, C. H. Adv.
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However, H. C. Brown et al. have extensively studied the steric effects
of isopropyl versus isobutyl in the context of borane adducts and have
shown that they have very similar steric demands or isobutyl is slightly
more sterically demanding than isopropyl. Therefore we are using the
following approximation: isopropyl A-value ≈ isobutyl A-value = 2.15.
See: (c) Brown, H. C.; Zaidlewicz, M.; Dalvi, P. V.; Narasimhan, S.;
Mukhopadhyay, A. Organometallics 1999, 18, 1305. (d) Brown, H. C.;
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We thank Deven Wang (Genentech) for collecting high
resolution mass spectra and Mengling Wong (Genentech) for
separating diastereomers of compounds 2, 7 and 8 by SFC for
characterization purposes. Kyle Clagg (Genentech) is also
thanked for providing us with intermediate 4.
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