The Catalyst-Controlled Regiodivergent Chlorination of Phenols

Article abstract of DOI:10.1021/acs.orglett.6b02650

Different catalysts are demonstrated to overcome or augment a substrate's innate regioselectivity. Nagasawa's bis-thiourea catalyst was found to overcome the innate para-selectivity of electrophilic phenol chlorination, yielding ortho-chlorinated phenols that are not readily obtainable via canonical electrophilic chlorinations. Conversely, a phosphine sulfide derived from 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) was found to enhance the innate para-preference of phenol chlorination.

Full text of DOI:10.1021/acs.orglett.6b02650

Letter
pubs.acs.org/OrgLett
The Catalyst-Controlled Regiodivergent Chlorination of Phenols
Sean M. Maddox,†,§ Andrew N. Dinh, Felipe Armenta, Joann Um, and Jeffrey L. Gustafson*
†,§
†
‡
,†
†Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, California 92182,
United States
‡
Department of Physical Sciences, Southwestern College, 900 Otay Lakes Road, Chula Vista, California 91910, United States
*
S Supporting Information
ABSTRACT: Different catalysts are demonstrated to overcome or augment a
substrate’s innate regioselectivity. Nagasawa’s bis-thiourea catalyst was found to
overcome the innate para-selectivity of electrophilic phenol chlorination, yielding
ortho-chlorinated phenols that are not readily obtainable via canonical electrophilic
chlorinations. Conversely, a phosphine sulfide derived from 2,2′-Bis(diphenyl-
phosphino)-1,1′-binaphthyl (BINAP) was found to enhance the innate para-preference
of phenol chlorination.
ryl chlorides are both versatile synthetic handles and
common functionalities in drug discovery. As such, there
nonfavored isomer when the substrate possess a strong innate
preference.
A
are numerous methodologies to access them, with electrophilic
aromatic substitution (EAS) representing a broadly utilized
There are relatively few examples of catalyst-controlled
regioselectivities in the arena of EAS, with seminal work by
1
−3
13,14
route. Traditional electrophilic halogenations
suffer from
Miller
on complex natural products exemplifying the small
15,16
several drawbacks such as a reliance on harsh reaction conditions,
reduced reactivity toward electron-poor arenes, and a lack of
regioselectivity across many substrate classes. While recent
molecule approaches. Alternatively, Lewis
has engineered
mutants of the enzyme RebH that can overcome the innate
regioselectivity of heterocycle chlorination. Herein we disclose a
novel approach to address these issues, in which we demonstrate
the ability of different catalysts to control the regioselectivity of
phenol halogenation in a divergent fashion.
4
−12
advances
have largely addressed the first two issues,
regioselectivity is still an unsolved problem as current electro-
philic halogenations rely on substrate-controlled regioselectivity
9
(Figure 1A) often resulting in a mixture of constitutional isomers.
We have recently disclosed a mild catalytic electrophilic
On the other hand, it becomes a synthetic challenge to obtain a
halogenation of arenes and heterocycles using catalytic Lewis
17−23
bases
(i.e., phosphine sulfide 1) to activate N-halosuccini-
mides (NXSs). These catalysts were able to effect the
chlorination of diverse arenes according to the innate preference
of a substrate with regioselectivities closely following those
8
,10,12
reported in literature.
Monitoring the course of the reaction
by 31P NMR (Figure S1) suggested the formation of an
24
intermediate with a large degree of phosphonium character,
which would be expected if the chemistry proceeds through a
2
5,26
catalyst−halenium
adduct such as 2 (Figure 1). This is
corroborated by DFT (Scheme S1) studies that predict
halogenation to proceed through such an intermediate.
As these data suggest the activated halenium is associated with
the catalyst, we hypothesized that the Lewis base catalyst
structure can alter the reaction outcome of electrophilic aromatic
halogenation. As a proof of concept, we chose to test this in the
context of the ortho-chlorination of phenols. Phenols are an
Received: September 3, 2016
Figure 1. Regioselectivities in the chlorination of phenols.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02650
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
36,37
important class of arenes that typically display a moderate to high
thiourea
(4) efficiently catalyzed this reaction and yielded
para-preference (see Figure 1; Table 1, entry 1). While bulky
a 1.0:2.0 3a:3b ratio (Table 1, entry 2). While 4 still favored 3b,
we were intrigued by the moderate increase (compared to 1) in
ortho- isomer 3a formed and decided to evaluate other thioureas.
A slight increase in the selectivity for 3a was observed with urea 5,
albeit at the expense of significantly reduced reactivity. We found
Table 1. Catalyst Exploration towards the ortho-Chlorination
of Phenol
38
that Nagasawa’s bis-thiourea (6) overcame the substrate’s
innate preference, yielding a 5.4:1.0 mixture of isomers favoring
3a (Table 1, entry 4). This ratio could be improved to 27:1.0 by
diluting the reaction concentration (Table 1, entry 8). This
noticeable effect on the regioselectivity is likely due to a decrease
in catalyst aggregation at lower concentration and is consistent
39
with recent work by Seidel. To put the efficiency of catalyst 6 in
‡
perspective, the ΔΔΔG between catalyst 6 and catalyst 1 toward
catalyst
(%)
solvent
conversion to
ΔΔΔG‡
f
ortho-chlorination is 2.77 kcal/mol, which would correspond to
approximately 98% ee in the realm of enantioselective catalysis.
To define the generality of this catalyst-controlled ortho-
chlorination, we applied catalyst 6 across a series of differentially
substituted phenols, observing predominantly ortho-chlorination
across the substrate set (Scheme 1). This was in contrast to
catalyst 1, which predominantly yielded para-chlorination. For
example, 6 effected the chlorination of phenol 8 to give an ortho/
para ratio (8a:8b) of 10:1.0, with 8a being isolated in 75% yield.
We observed a decrease in ortho-selectivity for 2-tert-butyl
b
c
d
entry
1
(molarity)
3a (%)
3a:3b
(kcal/mol)
1 (10)
CDCl3
0.05)
23
33
14
67
48
1.0:4.0
1.0:2.0
1.0:1.1
5.4:1.0
3.2:1.0
0
(
2
3
4
5
4 (10) CDCl3
0.41
0.76
1.82
1.49
(
0.025)
5 (10) CDCl3
(
0.025)
6 (10) CDCl3
(
0.05)
6 (10) CDCl3
(
0.05)
6
7
8
6 (10) C D (0.05)
55
75
83
6.4:1.0
6.9:1.0
27:1.0
1.92
1.96
2.77
6
6
Scheme 1. ortho-Selective Chlorination of Substituted
Phenols
6 (5)
C D (0.025
6 6
6 (10) CDCl3
(
0.025)
9
6 (5)
CDCl3
82
20
13
64
16
12:1.0
1.0:3.0
1.0:7.1
4.7:1.0
1.0:5.0
2.29
0.17
(
0.025)
10
11
12
13
1 (10) CDCl3
(
0.025)
7 (10) CDCl3
−0.33
1.73
(
0.05)
6 (10) CD Cl
2
2
(
0.025)
7 (10) CD Cl
−0.13
2
2
(
0.05)
a
All reactions were performed by addition of a catalyst, solvent, and
0
.03 mmol of 3 at rt, followed by the addition of 0.036 mmol of NCS.
b
c
Molarity of the reaction is in reference to 3. Percent conversion to
3
1
a was determined by H NMR and represents an average of three
trials using tetramethylsilane or tetrakis(trimethylsilyl)methane as an
d
1
internal standard. Isomeric ratios were determined by H NMR and
e
represent an average of three trials. We observed only minor
decreases in selectivities with CD Cl as the solvent, allowing us to
2
2
reliably use DCM as our solvent upon scale-up to mitigate loss of
f
‡
‡
‡
volatile products. ΔΔΔG = ΔΔG
− ΔΔG entry 1, with ortho-
entry#
‡
selectivity defined as positive ΔΔG and para-selectivity defined as
‡
negative ΔΔG .
3
,27
amines are known to effect the ortho-chlorination of phenols
a
Optimized reaction conditions were used with respect to the catalyst
b
c
these reactions operate under fairly harsh conditions (sulfuryl
(
see Table 1). Only the major product is shown. Reaction times and
1
chloride at 70 °C) and have been shown to have limited substrate
constitutional isomer ratios were determined by H NMR and
represent an average of two trials using tetramethylsilane or
tetakis(trimethylsilyl)methane (TTMSM) as an internal standard.
2
8
scope. Other commonly employed routes to ortho-chlorinated
phenols involve multistep processes that include arene
d
2
9,30
31,32
Isolated yields were determined on the 50−1000 mg scale, using
oxidation,
(
dehalogenation,
or O-Methoxymethyl
3
3,34
DCM as the solvent (due to volatility), and represent an average of
two trials (see Supporting Information). The selectivities observed
with catalyst 1 are included for comparison. With ortho-selectivity
MOM) directed lithiation.
A catalytic room temperature
e
ortho-selective electrophilic chlorination would represent a more
desirable approach that could be performed in one step with few
precautions, lending it several practical advantages over current
routes.
f
‡
defined as positive ΔΔG and para-selectivity defined as negative
‡
g
ΔΔG . Due to product volatility, an isolated yield could not be
1
reported; therefore, % conversion was reported as determined by H
35
h
We began these studies by evaluating several privileged
catalyst structures that also possessed Lewis basic functional
NMR using TTMSM as an internal standard. Both ortho products (a
and c) combined to simplify calculation. Assuming >20:1 ortho/para
i
1
8
groups that are known to activate NXS. Schreiner’s
with 6.
B
DOI: 10.1021/acs.orglett.6b02650
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted 9 (ortho/para ratio of 3:1), perhaps due to the bulky
substituent interfering with a catalyst−substrate interaction.
Nonetheless, we were able to isolate 9a with a 70% yield. Nitrile-
containing 10 and 2-iodophenol (11) also proved to be good
substrates, affording ortho/para ratios of 5.7:1 and 8:1,
respectively.
Scheme 2. Augmenting the Innate Chlorination of Phenol
The chlorination of meta-substituted phenols also proceeded
with ortho-selectivity in the presence of 6. For example, the
chlorination of 3-fluorophenol (12) yielded an excellent 16.0:1.0
12a:12b ratio. Substrates with less electronically withdrawing
meta-substituents were also chlorinated ortho- to the phenol by 6;
however, now varying degrees of chlorination at the more
hindered ortho-position were observed inline with expected
electronic trends (see substrates 13−16 in Scheme 1). 17
possessed particularly interesting selectivity as 6 primarily
effected halogenation at the more hindered ortho-position to
give predominantly 17c (1.0:0:5.5 ratio of 17a:17b:17c). From
an energetic perspective, catalyst 6 was less effective on these
‡
substrates than phenol; however, the ΔΔΔG between catalyst 6
and catalyst 1 were still quite good, corresponding to a range of
8
5% to 96% ee when an analogy to enantioselective catalysis is
made.
With an ortho-selective catalyst in hand we then turned our
a
Optimized reaction conditions were used with respect to the catalyst
b
c
(see Table 1). Only the major product is shown. Reaction times and
attention to catalysts that augment the innate para-selectivity of
phenols, finding that Bis(diphenylphosphino)-1,1′-binaphthyl
1
constitutional isomer ratios were determined by H NMR and
represent an average of two trials using tetramethylsilane or
tetakis(trimethylsilyl)methane as an internal standard. Isolated yields
(
BINAP)-derived phosphine sulfide 7 was able to improve upon
d
the innate para-selectivity of phenol, yielding a 3a:3b ratio of
were determined on the 50−1000 mg scale, using DCM as the solvent
1
.0:7.1 (Table 1, entry 11).
(due to volatility), and represent an average of two trials (See SI).
We then evaluated catalyst 7 across a set of substrates (Scheme
). In general, 7 was found to yield markedly improved para-
e
The selectivities observed with catalyst 1 are included for comparison.
f
‡
2
With ortho-selectivity defined as positive ΔΔG and para-selectivity
‡
g
selectivities compared to those of 1. For example, 7 effected the
chlorination of phenols 8 and 9 with ortho/para ratios of 1.0:12
defined as negative ΔΔG . Due to product volatility, an isolated yield
could not be reported; therefore, % conversion was reported as
1
h
(
compared to 1.0:3.2 and 1.0:4.0 respectively by 1). We also
determined by H NMR using TTMSM as in internal standard. Both
ortho products (a and c) combined to simplify calculation.
observed a similar degree of para augmentation with 7 for nitrile
containing 10 (10a:10b of 1.0:7.4 vs 1.0:2.5 for 1) and 2-
iodophenol (11) (ortho/para ratio of 1.0:20 vs 1:5.4). Catalyst 7
also augmented the para-selectivity of meta-substituted phenols
when compared to catalyst 1. For example, while fluorophenol
2A), albeit with a significant amount of polybromination, while 6
gave an observed 3c:3d ratio of 3.3:1.0. Ortho-substituted
phenols 8 and 18 proceeded more smoothly, with 1 yielding
predominantly para-brominated 8d and 18b, and catalyst 6
favoring bromination ortho- to the hydroxy group each time
(8c:8d ratio of 5:1; 18a:18b ratio of 4:1). It should be noted that
when using 1.2 equiv of NBS we observed some dibromination
which complicated purification and resulted in isolated yields
that were lower than observed NMR conversions.
We also evaluated the chlorination of substrates that possessed
multiple directing groups such as guaiacol (19), finding catalyst 1
to effect chlorination exclusively para- to the phenol giving 19b
in high yields. Interestingly, catalyst 6 was able to overcome this
large substrate preference to yield ortho-chlorinated 19a as the
major product, however, with a more modest ratio than other
substrates in Scheme 1. It is worth mentioning that this modest
selectivity is due to the large innate para- preference of 19, as
from an energy perspective catalyst 6 overcomes roughly 2.1
kcal/mol, comparable, if not better, than many of the substrates
in Scheme 1.
12 gave a ratio of 12a:12b as 1.1:1.0 with catalyst 1, chlorination
of 12 with catalytic 7 altered the reaction outcome to give para-
halogenated 12b as the major product (ratio of 12a:12b as
1.0:2.1). 7 also resulted in increases in para selectivity of 2−3-
fold for phenols 14, 16, and 17. It should be noted that, for some
phenols, such as 13 and 15, catalyst 7 increased selectivity
minimally. Finally, the chlorination of ester-containing 17 was
seemingly unselective with catalyst 1, resulting in a mixture of
1
7a:17b:17c as 1.0:7.0:6.0, yet in the presence of 7, the
chlorination proceeded to yield a para-favoring mixture of
7a:17b:17c as 1.0:13:6.5. While the increases in para selectivity
1
are moderate, the ability to augment para-selectivities when using
catalyst 7 over catalyst 1 complements the catalyst-directed
ortho-chlorinations in Scheme 1 and serves as another proof of
concept that catalyst structure can both augment (as with 7) or
override (as with 6) innate regioselectivities.
We next probed whether these catalysts could also effect
regioselective brominations. While there are robust conditions
In conclusion, we have demonstrated that the catalyst
structure of Lewis bases can influence the regioselectivity of
the electrophilic halogenation of phenols. A particularly exciting
aspect of this work is the observed reversal of regioselectivity by
Nagasawa’s bis-thiourea 6, presumably through a mechanism in
which one thiourea interacts with the phenol hydroxy group, and
the other activates NCS through a Lewis basic (analogous to that
40
for ortho-bromination, catalyst controlled bromination might
find utility in late stage functionalization. In these studies we
found little difference between catalysts 1 and 7, with both
yielding predominantly para-brominated products; however, as
with chlorination, 6 overcame this innate para-preference to give
mostly ortho-brominated products. For example, phenol 3
yielded excellent regioselectivities (3c:3d ratio of 1.0:11, Figure
depicted in Figure 1) or a Bro
̈
nsted acidic manifold (H-bonding
C
DOI: 10.1021/acs.orglett.6b02650
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) Qian, G.; Hong, X.; Liu, B.; Mao, H.; Xu, B. Org. Lett. 2014, 16,
5
(
294.
5) Guo, H.; Chen, M.; Jiang, P.; Chen, J.; Pan, L.; Wang, M.; Xie, C.;
Zhang, Y. Tetrahedron 2015, 71, 70.
(6) Zhang, Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005, 2837.
(7) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(8) Rodriguez, R. A.; Pan, C.-M.; Yabe, Y.; Kawamata, Y.; Eastgate, M.
D.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 6908.
9) Maddox, S. M.; Nalbandian, C. J.; Smith, D. E.; Gustafson, J. L. Org.
Lett. 2015, 17, 1042.
10) Bovonsombat, P.; Sophanpanichkul, P.; Pandey, A.; Tungsirisurp,
(
(
S.; Limthavornlit, P.; Chobtumskul, K.; Kuhataparuk, P.; Sathityatiwat,
S.; Teecomegaet, P. Tetrahedron Lett. 2015, 56, 2193.
(11) Wang, M.; Zhang, Y.; Wang, T.; Wang, C.; Xue, D.; Xiao, J. Org.
Lett. 2016, 18, 1976.
(12) Samanta, R. C.; Yamamoto, H. Chem. - Eur. J. 2015, 21, 11976.
(13) Pathak, T. P.; Miller, S. J. J. Am. Chem. Soc. 2012, 134, 6120.
(14) Giuliano, M. W.; Miller, S. J. In Topics in Current Chemistry;
Kawabata, T., Ed.; Springer International Publishing: Cham, 2016; pp
57−201.
15) Payne, J. T.; Andorfer, M. C.; Lewis, J. C. Angew. Chem., Int. Ed.
013, 52, 5271.
1
(
2
(16) Payne, J. T.; Lewis, J. C. Synlett 2014, 25, 1345.
(17) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1
(
1
560.
18) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U. S. A. 2010,
07, 20655.
(19) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014,
136, 5627.
20) Tan, C. K.; Yeung, Y.-Y. Chem. Commun. (Cambridge, U. K.) 2013,
9, 7985.
21) Tay, D. W.; Leung, G. Y. C.; Yeung, Y.-Y. Angew. Chem., Int. Ed.
Figure 2. Regiodivergent bromination and the ortho-chlorination of
guaiacol.
(
4
(
with NCS carbonyl). Mechanistic studies to understand how this
chemistry works are ongoing. These results represent a novel and
facile route to access arene substitution patterns that are not
currently readily available. More broadly, these results represent
a key proof of concept that a catalyst can indeed alter the reaction
outcome of electrophilic halogenation.
2014, 53, 5161.
(22) Wong, Y. C.; Ke, Z.; Yeung, Y.-Y. Org. Lett. 2015, 17, 4944.
(
2
(
23) Ke, Z.; Wong, Y. C.; See, J. Y.; Yeung, Y.-Y. Adv. Synth. Catal.
016, 358, 1719.
24) Quin, L. D.; Williams, A. Practical Interpretation of P-31 NMR
Spectra and Computer Assisted Structure Verification; Advanced
Chemistry Development, Inc.: 2004.
(
25) Ashtekar, K. D.; Marzijarani, N. S.; Jaganathan, A.; Holmes, D.;
ASSOCIATED CONTENT
Supporting Information
■
Jackson, J. E.; Borhan, B. J. Am. Chem. Soc. 2014, 136, 13355.
(26) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed.
*
S
2
012, 51, 10938.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02650.
(
(
(
27) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 2004, 45, 8471.
28) Yu, M.; Snider, B. B. Org. Lett. 2011, 13, 4224.
29) Ohkubo, K.; Hirose, K.; Fukuzumi, S. Chem. - Eur. J. 2015, 21,
Experimental procedures and analytical data for regiose-
1
lective analyses and all new compounds, including H and
2855.
(30) Kotouco
Dvora ova, H.; Cibulka, R. Org. Biomol. Chem. 2014, 12, 2137.
31) Dong, Z.; Le, X.; Liu, Y.; Dong, C.; Ma, J. J. Mater. Chem. A 2014,
, 18775.
(32) Keane, M. A.; Gomez-Quero, S.; Cardenas-Lizana, F.; Shen, W.
ChemCatChem 2009, 1, 270.
33) Marzi, E.; Mongin, F.; Spitaleri, A.; Schlosser, M. Eur. J. Org.
Chem. 2001, 2001, 2911.
34) Townsend, C. A.; Davis, S. G.; Christensen, S. B.; Link, J. C.;
Lewis, C. P. J. Am. Chem. Soc. 1981, 103, 6885.
13
C spectra are included in the Supporting Information
̌ ́ ́ ́
va, H.; Strnadova, I.; Kovandova, M.; Chudoba, J.;
̌
k
́
́
(
PDF)
(
2
AUTHOR INFORMATION
Corresponding Author
■
*
(
E-mail: jgustafson@mail.sdsu.edu.
Author Contributions
(
§
S.M.M. and A.N.D. contributed equally.
(
(
(
(
35) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
36) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
37) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
38) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was funded by SDSU start up funds as well as the
SDSU Presidential Leadership Fund.
Tetrahedron Lett. 2004, 45, 5589.
(39) Mittal, N.; Lippert, K. M.; De, C. K.; Klauber, E. G.; Emge, T. J.;
Schreiner, P. R.; Seidel, D. J. Am. Chem. Soc. 2015, 137, 5748.
■
(40) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A. Bull.
Chem. Soc. Jpn. 1993, 66, 1576.
REFERENCES
1) Smith, J. R. L.; McKeer, L. C. Tetrahedron Lett. 1983, 24, 3117.
2) Watson, W. D. J. Org. Chem. 1985, 50, 2145.
3) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 1995, 36, 3893.
■
(
(
(
D
DOI: 10.1021/acs.orglett.6b02650
Org. Lett. XXXX, XXX, XXX−XXX