Dirhodium-catalyzed C-H arene amination using hydroxylamines

Article abstract of DOI:10.1126/science.aaf8713

Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals, agrochemicals, and functional materials, as well as in bioactive natural products. However, there is a dearth of generally applicablemethods for the direct replacement of aryl hydrogens with NH₂/NH(alkyl) moieties. Here, we present a mild dirhodium-catalyzed C-H amination for conversion of structurally diverse monocyclic and fused aromatics to the corresponding primary and N-alkyl arylamines using NH₂/NH(alkyl)-O-(sulfonyl)hydroxylamines as aminating agents; the relatively weak RSO₂O-N bond functions as an internal oxidant. The methodology is operationally simple, scalable, and fast at or below ambient temperature, furnishing arylamines in moderate-to-good yields and with good regioselectivity. It can be readily extended to the synthesis of fused N-heterocycles.

Full text of DOI:10.1126/science.aaf8713

RESEARCH
| REPORTS
REFERENCES AND NOTES
ORGANIC CHEMISTRY
1. B. J. Wood, M. J. Walter, J. Wade, Nature 441, 825–833 (2006).
2. D. C. Rubie, F. Nimmo, H. J. Melosh, in Evolution of the Earth,
D. J. Stevenson, Ed., vol. 9 of Treatise on Geophysics, G. Schubert,
Ed. (Elsevier, ed. 2, 2015) pp. 43–79.
3. U. Mann, D. J. Frost, D. C. Rubie, H. Becker, A. Audétat,
Geochim. Cosmochim. Acta 84, 593–613 (2012).
4. R. J. Walker et al., Chem. Geol. 411, 125–142 (2015).
5. C.-L. Chou, Proc. Lunar Planet Sci. 9, 219–230 (1978).
6. S. A. Jacobson et al., Nature 508, 84–87 (2014).
7. M. J. Walter, E. Cottrell, Earth Planet. Sci. Lett. 365, 165–176
(2013).
Dirhodium-catalyzed C-H arene
amination using hydroxylamines
Mahesh P. Paudyal,1 Adeniyi Michael Adebesin,1 Scott R. Burt,2 Daniel H. Ess,2
Zhiwei Ma,3 László Kürti,3 John R. Falck1*
8. D. C. Rubie et al., Icarus 248, 89–108 (2015).
9. D. P. O’Brien, K. J. Walsh, A. Morbidelli, S. N. Raymond,
A. M. Mandell, Icarus 239, 74–84 (2014).
10. S. A. Jacobson, A. Morbidelli, Philos. Trans. A Math. Phys. Eng.
Sci. 372, 20130174 (2014).
11. K. J. Walsh, A. Morbidelli, S. N. Raymond, D. P. O’Brien,
A. M. Mandell, Nature 475, 206–209 (2011).
12. Materials and methods are available as supplementary
materials on Science Online.
Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals,
agrochemicals, and functional materials, as well as in bioactive natural products. However,
there is a dearth of generally applicable methods for the direct replacement of aryl hydrogens
with NH2/NH(alkyl) moieties. Here, we present a mild dirhodium-catalyzed C-H amination for
conversion of structurally diverse monocyclic and fused aromatics to the corresponding
primary and N-alkyl arylamines using NH2/NH(alkyl)-O-(sulfonyl)hydroxylamines as
aminating agents; the relatively weak RSO2O-N bond functions as an internal oxidant. The
methodology is operationally simple, scalable, and fast at or below ambient temperature,
furnishing arylamines in moderate-to-good yields and with good regioselectivity. It can
be readily extended to the synthesis of fused N-heterocycles.
13. R. Deguen, P. Olson, P. Cardin, Earth Planet. Sci. Lett. 310,
303–313 (2011).
14. D. C. Rubie et al., Earth Planet. Sci. Lett. 301, 31–42 (2011).
15. J. de Vries et al., Prog. Earth Planet. Sci. 3, 7 (2016).
16. V. Laurenz, D. C. Rubie, D. J. Frost, A. K. Vogel, Geochim.
Cosmochim. Acta 10.1016/j.gca.2016.08.012 (2016).
17. K. Lodders, Astrophys. J. 591, 1220–1247 (2003).
18. P. Cassen, Meteor. Planet. Sci. 31, 793–806 (1996).
19. A. Boujibar et al., Earth Planet. Sci. Lett. 391, 42–54 (2014).
20. G. Dreibus, H. Palme, Geochim. Cosmochim. Acta 60, 1125–1130 (1996).
21. H. Palme, H. St. C. O’Neill, in The Mantle and Core, R. W. Carlson,
Ed., vol. 3 of Treatise on Geochemistry, H. D. Holland, K. K. Turekian,
Eds. (Elsevier-Pergamon, ed. 2, 2014), pp. 1–39.
22. T. S. Kruijer et al., Geochim. Cosmochim. Acta 99, 287–304 (2012).
23. T. W. Dahl, D. J. Stevenson, Earth Planet. Sci. Lett. 295,
177–186 (2010).
24. H. St. C. O’Neill, Geochim. Cosmochim. Acta 55, 1159–1172 (1991).
25. P. S. Savage et al., Geochem. Persp. Lett. 1, 53–64 (2015).
26. J. A. Mavrogenes, H. St. C. O’Neill, Geochim. Cosmochim. Acta
63, 1173–1180 (1999).
27. V. S. Solomatov, in Origin of the Earth and Moon, R. M. Canup,
K. Righter, Eds. (Univ. of Arizona Press, 2000), pp. 323–338.
28. Y. Abe, Phys. Earth Planet. Inter. 100, 27–39 (1997).
29. D. C. Rubie, H. J. Melosh, J. E. Reid, C. Liebske, K. Righter,
Earth Planet. Sci. Lett. 205, 239–255 (2003).
30. V. Laurenz et al., Geochim. Cosmochim. Acta 108, 172–183 (2013).
31. H. Terasaki, D. J. Frost, D. C. Rubie, F. Langenhorst, Earth
Planet. Sci. Lett. 273, 132–137 (2008).
32. H. Becker et al., Geochim. Cosmochim. Acta 70, 4528–4550 (2006).
33. M. Fischer-Gödde, H. Becker, Geochim. Cosmochim. Acta 77,
135–156 (2012).
34. W. D. Maier et al., Nature 460, 620–623 (2009).
35. H. Rizo et al., Science 352, 809–812 (2016).
36. N. Dauphas, A. M. Davis, B. Marty, L. Reisberg, Earth Planet.
Sci. Lett. 226, 465–475 (2004).
rylamine motifs (1, 2) are prevalent in natu-
ral products, pharmaceuticals, agrochem-
icals, functional materials, and dyestuffs,
as well as in many synthetic reagents and
catalysts (3–5). Most traditional methods
Many elegant atom- and step-efficient protocols
have been introduced, but virtually all require a
directing group, while others need an excess of
arene, require high temperatures, or generate
amides, imides, and sulfonamides instead of free
amines (20–31). A noteworthy exception is the
photoredox-driven process of Nicewicz (32) and
colleagues that circumvents many of the pre-
ceding limitations.
Extensive density functional theory (DFT) cal-
culations of the dirhodium-catalyzed olefin azir-
idination reported previously by our laboratories
(33) suggested that the reactive rhodium-nitrene
complex might exist in a protonated form in the
presence of a weakly basic counterion and that
this species could follow a different reaction
manifold. This was corroborated by analysis of
minor by-products from the aziridination of dif-
ferent substrates and the behavior of structurally
varied nitrogen donors. After a systematic in-
vestigation, proof-of-principle for arene ami-
nation versus aziridination was demonstrated
(Fig. 1). Treatment of 1-allyl-2-methoxybenzene
(o-allylanisole, 1) with O-(2,4-dinitrophenyl)-
A
for their synthesis from a corresponding C(sp2)–
H bond involve multistep sequences and/or harsh
conditions (6–8). In many instances, the initial
product (nitro, azide, azo, nitroso, chloronitroso,
amide/imide/sulfonamide, or imine) requires
one or more additional steps before arriving at
a free amine (6). The amination of organic anions
is a useful and direct alternative (9), but is gen-
erally restricted to the introduction of NR1R2
(R1, R2 ≠ H) and is not applicable to base-sensitive
substrates. The seminal studies of Ullmann and
Goldberg into metal-mediated arene C(sp2)-N
bond formation at the beginning of the 20th
century were harbingers (10) of more efficient
palladium-catalyzed cross-couplings between aro-
matic halides/sulfonates and ammonia or nitrogen
surrogates developed independently by Hartwig
(11) and Buchwald (12) in the early 1990s. In turn,
a steady succession of technical improvements,
up to the present time, has been offered with the
aim of mitigating the original stringent Hartwig-
Buchwald reaction conditions (13–16). All of these
procedures, however, are restricted by the need
for a prefunctionalized arene.
37. F. Albarède, Nature 461, 1227–1233 (2009).
38. J. Wade, B. J. Wood, J. Tuff, Geochim. Cosmochim. Acta 85, 58–74 (2012).
39. G. Helffrich, S. Kaneshima, Nature 468, 807–810 (2010).
1Division of Chemistry, Department of Biochemistry,
University of Texas Southwestern Medical Center, Dallas,
TX 75390, USA. 2Department of Chemistry and Biochemistry,
Brigham Young University, Provo, UT 84602, USA. 3Department
of Chemistry, Rice University, BioScience Research
Collaborative, Houston, TX 77005, USA.
ACKNOWLEDGMENTS
D.C.R., V.L., S.A.J., A.M., and H.P. were supported by the European
Research Council Advanced Grant ACCRETE (Accretion and Early
Differentiation of the Earth and Terrestrial Planets; contract number
290568). A.K.V. was supported by the German Science Foundation
(DFG) Priority Programme SPP1385, “The first 10 million years of the
solar system – a planetary materials approach” (grant Ru1323/2). We
thank H. J. Melosh and R. J. Walker for discussions and three reviewers
for their helpful and constructive comments. Data files with final results
are available in the supplementary materials.
In more recent years, much attention has been
paid to catalytic, direct arene aminations (17–19).
*Corresponding author. Email: j.falck@utsouthwestern.edu
Fig. 1. A marked shift
in chemoselectivity
arises with different
aminating agents.
o-Allylanisole (1)
undergoes chemose-
lective olefin aziridina-
tion in the presence of
catalytic Rh2(esp)2 (6)
and aminating agent
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/353/6304/1141/suppl/DC1
Materials and Methods
Supplementary Text
Figs. S1 to S4
Tables S1 and S2
References (40–62)
Databases S1 and S2
DPH (2) in 2,2,2-trifluoroethanol (TFE = CF3CH2OH) to give 3. Changing the aminating agent to
TsONHMe (4a) furnishes the corresponding N-Me aniline (5).
5 April 2016; accepted 17 August 2016
10.1126/science.aaf6919
1144 9 SEPTEMBER 2016 • VOL 353 ISSUE 6304
sciencemag.org SCIENCE

RESEARCH
| REPORTS
hydroxylamine (2: DPH) (34) and catalytic Rh2
(esp)2 (Du Bois’ catalyst, 6: 5 mol %) in 2,2,2-
trifluoroethanol (TFE) at 0°C afforded the cor-
responding aziridine (3) as the sole product,
whereas use of N-methyl-O-tosylhydroxylamine
(4a) (35) as the aminating agent under other-
wise identical conditions furnished exclusively
the arene amination adduct 3-allyl-4-methoxy-N-
methylaniline (5). Consequently, a more detailed
study of the C-H arene amination was begun and
ultimately led to a versatile, regioselective, oper-
ationally simple and mild dirhodium-catalyzed
direct arene amination suitable for both inter-
molecular and intramolecular applications. The
relatively weak N–O bond of the aminating agents,
many of which are commercial or readily prepared
(33–37), functions as an internal oxidant when
cleaved during the catalytic amination process,
thus obviating the need for addition of an ex-
ternal oxidant to the reaction mixture. Also, the
synchronous release of a stoichiometric amount
of arylsulfonic acid during the amination is crit-
ical because it protonates the arylamines, which
would otherwise inactivate the Rh catalyst. In
some instances, acid-sensitive functionality such
as epoxides and acetals do not survive.
Mesitylene (7a) was selected as a model arene
to optimize reaction parameters. Use of 2 mol %
Rh2(esp)2 and 1.5 equivalents of aminating agent
4a in TFE as solvent smoothly generated N-
methylaniline 8a (75%) in just 30 min at 0°C (Fig.
2, entry 1); comparable yields were obtained with
1 and 0.5 mol % catalyst, except that the latter
required 1 hour for complete consumption of
starting material. Combinations of TFE with
CH2Cl2 or MeOH in ratios up to 1:1 were suit-
able, but aminations run in EtOH or MeOH as
the only solvent delivered poor yields (~10 to
20%) and those run in only DMF, CH3CN, THF,
toluene, and dioxane failed. Among alternative
Rh-catalysts, Rh2(OAc)4 and Rh2(C8H15O2)4 were
the next best with moderate yields (~40 to 45%),
whereas the performance by Rh2(TFA)4 was poor.
Results from other catalysts are summarized in
table S1. Generally, reactions were quenched as
soon as the substrate was completely consumed
to minimize by-product formation. Air and water
(5% v/v) were well tolerated, makingthismethod-
ology operationally convenient.
The successful transfer of a nBuNH- unit to 7a
from TsONHnBu (4b), affording 8b in 52% yield
(Fig. 2, entry 2), suggested that more
complex amino moieties should also
be suitable. For the introduction of
NH2 into 7a, we used 2,4,6-Me3C6H2S
(O)2ONH2 (36) (4c, 2 equiv.) as ami-
nating agent because of its greater
stability at room temperature com-
pared with TsONH2 (37). Although all
of 4c was consumed, a considerable
amount of unreacted 7a was recov-
ered and a modest yield (49%) of 8c
was realized (entry 3). By contrast,
the simple and expedient generation
of the aminating agent in situ from
2,4,6-Me3C6H2S(O)2ONHtBoc (4d, 1.5
equiv.) and CF3CO2H (2 equiv.) proved
quite effective and boosted the yield
of 8c to 70% (entry 4), although the re-
action was much slower than in the
case of aminating agent 4c (entry 3)
and appeared to be dependent on the
rate of tBoc cleavage.
The results from other representa-
tive arenes are also summarized in
Fig. 2. Despite having only a single
aliphatic substituent, cyclopropylben-
zene (7d) was well behaved, affording a
1:1 para-/ortho-mixture (8d and 8e) in
20 min at 0°C with no evidence of ad-
dition to the strained three-membered
ring (entry 5). The directing effect in
favor of the para-isomer was more
pronounced with anisole (7f) and led
to a 16:1 distribution of 8f and 8g
(entry 6). This effect completely domi-
nated in veratrole (7h) that gave 8h as
the predominant regioisomer (entry 7)
and was equally evident in the con-
version of 1,3-dimethyoxybenzene (7i)
into 8i, although a minor amount (6%)
of the ortho-isomer 8j was found de-
spite the increased steric congestion
at this site (entry 8). Addition of ace-
tic acid to the reaction solvent for the
latter three examples (entries 6 to 8)
improved the yields and suppressed
the formation of mauve-colored by-
Fig. 2. Direct intermolecular amination of arenes. Reactions were conducted on a 0.1- to 0.5-mmole scale at
0.1 M using 2,2,2-trifluoroethanol (TFE = CF3CH2OH) as solvent or using mixtures of TFE and other solvents as
indicated.
products that we assume arose from
further oxidation of the aminated ad-
ducts. The ortho/para-directing effect
SCIENCE sciencemag.org
9 SEPTEMBER 2016 • VOL 353 ISSUE 6304 1145

RESEARCH
| REPORTS
in very good combined yield, whereas
only one regioisomer 8w (entry 19)
was obtained from the parent phenol,
estrone (7w), thus demonstrating
applicability to substrates containing
potentially sensitive benzylic, tertiary,
and a-keto hydrogens. The scope was
further defined with the amination
of methyl naproxen 7x to 8x (entry
20) and morphine derivative 7y to
8y (entry 21). The latter required the
addition of p-toluenesulfonic acid
(2.5 equiv.) to ensure that the ter-
tiary amine was fully protonated to
avoid passification of the catalyst.
The intramolecular version of the
amination proved quite facile and rep-
resents one of the mildest and most
efficient aza-annulations currently
available to the practitioner (Fig. 3)
(38, 39). The enabling amination func-
tionality was introduced in uniformly
good yields via the Mitsunobu inver-
sion under standard conditions from
the corresponding alcohols. Acidic
cleavage of the tBoc and subsequent
in situ amination proceeded at 0°C.
Fused aza-annulated bicycles were
created in good yields irrespective
of additional ring substituents,
10a→11a (entry 1), electron-donating,
10b→11b (entry 2), or electron-
Fig. 3. Direct intramolecular cyclization (aza-annulation) of arenes. Cyclizations were conducted at 0.1 M
using 2,2,2-trifluoroethanol (TFE = CF3CH2OH) as solvent on a 0.1- to 0.3-mmol scale unless otherwise indicated.
of electron-donating substituents is typical for
electrophilic aromatic additions; the preference
for the para- versus ortho-isomer might reflect
the steric demand of the Rh-nitrenoid complex.
Consistent with these results, aromatics with
only electron-withdrawing substituents (e.g., CF3
and CN) fail to aminate under these reaction
conditions.
To validate the suitability of this methodology
for late-stage functionalization of complex mole-
cules, O-methylestrone (7u) was smoothly con-
verted to a mixture of 8u and 8v (1:7.2, entry 18)
withdrawing functionality, 10c→11c (entry 3)
and 10d→11d (entry 4). Control studies of
the reaction of 10b confirmed that there was
less than 2% of the ortho-annulation product,
Aryl bromide 7k (entry 9) and terminal alkyl
bromide 7l (entry 10) endured to deliver 8k and
a mixture of 8l/8m (3:1), respectively, leaving the
halogens available for further manipulation, if
desired. The presence of some functional groups,
however, partially retard amination; e.g., exposure
of benzyl alcohol 7n to the standard amination
conditions generated a modest amount of 8n
(42%) after 2 hours (entry 11); by contrast, pro-
tection as silyl ether 7o resulted in a much im-
proved yield of 8o (68%) (entry 12). Fortunately, a
synthetically useful yield of amine could be ob-
tained even in the presence of an electron-
withdrawing substituent, e.g., 7p→8p (entry 13).
The amination process was also extended to
fused aromatics: Naphthalene (7q) and 1,4-
dimethylnapthalene (7r) gave rise to N-methyl-1-
naphthylamine (8q, entry 14) and N-methyl-1,4-
dimethyl-2-naphthylamine (8r, entry 15), respec-
tively, and 2-methoxynaphthalene (7s) readily un-
derwent amination to give 8s in 85% yield on a
0.5-mmol scale and in 80% yield on a 5-mmol scale
(entry 16). The smooth amination of 2-methoxy-6-
bromonaphthalene (7t) into N-methyl-2-methoxy-
6-bromo-1-naphthylamine (8t, entry 17) succinctly
illustrates the chemo- and regioselectivities of this
methodology.
Fig. 4. Proposed intermediates leading to amination versus aziridination and control study of
arene amination versus benzylic C-H insertion.
1146 9 SEPTEMBER 2016 • VOL 353 ISSUE 6304
sciencemag.org SCIENCE

RESEARCH
| REPORTS
8-methoxy-1,2,3,4-etrahydroquinoline, based on 13C–
nuclear magnetic resonance analysis of the crude
reaction product (figs. S5 and S6). Secondary al-
cohols likewise participated readily in the Mit-
sunobu and aza-annulation reactions, 9e→10e→11e
(entry 5). This two-step sequence, when con-
ducted using the chiral alcohol 9f, showed no
loss of stereochemical integrity (entry 6). Incor-
poration of a heteroatom into the ring closure, e.g.,
9g→10g→11g (entry 7), did not perturb the che-
mistry and provided easy access to the dihydro-
benzoxazine class of heterocycles. The yield declined
somewhat for making the five-membered dihy-
droindole 11h from alcohol 9h (entry 8), but
improved for the seven-membered tetrahydro-
benzazepine 11i from 9i (entry 9).
As a beginning toward gaining insight into the
mechanism of the amination, a 1:1 mixture of
naphthalene (7q) and 7q-d8 was treated with a
limited amount of amination reagent (4a, 0.5
equiv.) under otherwise standard reaction condi-
tions. Samples were taken and quenched at 10,
20, 30, and 40 min. Analysis via selected ion
monitoring–liquid chromatography–mass spec-
trometry revealed that the product ratios remained
constant at ~1:1, a ratio inconsistent with an orga-
nometallic C-H activation pathway, which would
typically manifest ~3:1 or higher ratios (40, 41).
Based on DFT calculations, we previously sug-
gested that aziridination of alkenes involves the
dirhodium-nitrenoid intermediate B shown in
Fig. 4 that arises from overall NH transfer from the
DPH-aminating reagent to the dirhodium catalyst
(33). In contrast, reaction of O-tosylhydroxylamine
reagents with the dirhodium catalyst favor inter-
mediate A because TsO– is weakly basic and the
equilibrium with intermediate B lies far to the
left. The chemoselectivity might be explained by
the more electrophilic nature of intermediate A
versus nitrenoid B. This preliminary hypothesis
is consistent with the observation that moderate-to-
strong bases such as K2CO3, Et3N, and pyridine
completely inhibit amination, but not aziridina-
tion. Moreover, addition of TsOH (1.5 equiv.) to
the reaction of 1 with 2,4-DNPONHMe (12) pro-
duced only the arene amination adduct 5 and no
aziridine. As an additional control, it was shown
that the presence of 2,4-DNP-OH (1.5 equiv.) did
not alter the reaction manifold in favor of aziridi-
nation when 4a was used as the aminating reagent
and only 5 was observed.
REFERENCES AND NOTES
30. C. Suzuki, K. Hirano, T. Satoh, M. Miura, Org. Lett. 17,
1597–1600 (2015).
31. K. Takamatsu, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 80,
3242–3249 (2015).
32. N. A. Romero, K. A. Margrey, N. E. Tay, D. A. Nicewicz, Science
349, 1326–1330 (2015).
1. R. Hili, A. K. Yudin, Nat. Chem. Biol. 2, 284–287 (2006).
2. A. Ricci, Ed., Amino Group Chemistry: From Synthesis to the
Life Sciences (Wiley-VCH, 2008).
3. R. J. Angelici, Reagents for Transition Metal Complex and
Organometallic Synthesis (Wiley-Interscience, New York, 1990), vol. 28.
4. A. Dalla Cort et al., J. Org. Chem. 70, 8877–8883 (2005).
5. N. R. Candeias, L. C. Branco, P. M. P. Gois, C. A. M. Afonso,
A. F. Trindade, Chem. Rev. 109, 2703–2802 (2009).
6. J. F. Hartwig, S. Shekhar, Q. Shen, F. Barrios-Landeros, Chem.
Anilines 1, 455–536 (2007).
7. Y.-S. Xie et al., Tetrahedron Lett. 54, 5151–5154 (2013).
8. J.Yu,P.Zhang, J.Wu, Z.Shang, Tetrahedron Lett. 54, 3167–3170 (2013).
9. T. Daskapan, ARKIVOC 2011, 230–262 (2011).
10. K. Kunz, U. Scholz, D. Ganzer, Synlett (15): 2428–2439 (2003).
11. J. F. Hartwig, Acc. Chem. Res. 41, 1534–1544 (2008).
12. D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 47, 6338–6361 (2008).
13. N. Xia, M. Taillefer, Angew. Chem. Int. Ed. 48, 337–339 (2009).
14. X. Zeng, W. Huang, Y. Qiu, S. Jiang, Org. Biomol. Chem. 9,
8224–8227 (2011).
15. R. J. Lundgren, M. Stradiotto, Aldrichim Acta 45, 59–65 (2012).
16. T. Maejima et al., Tetrahedron 68, 1712–1722 (2012).
17. H. M. L. Davies, X. Dai, Synthetic reactions via C-H bond
activation: Carbene and nitrene C-H insertion, in
Comprehensive Organometallic Chemistry III, R. H. Crabtree,
D. M. P. Mingos, Eds. (Elsevier, 2007), vol. 10, pp. 167–212.
18. J. Jiao, K. Murakami, K. Itami, ACS Catal. 6, 610–633 (2016).
19. P. Starkov, T. F. Jamison, I. Marek, Chemistry 21, 5278–5300 (2015).
20. W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
127, 14560–14561 (2005).
21. K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto, K. Hiroya, Org.
Lett. 9, 2931–2934 (2007).
22. G. Brasche, S. L. Buchwald, Angew. Chem. Int. Ed. 47, 1932–1934 (2008).
23. K. Inamoto, T. Saito, K. Hiroya, T. Doi, J. Org. Chem. 75,
3900–3903 (2010).
33. J. L. Jat et al., Science 343, 61–65 (2014).
34. Z. Yang, Synlett 25, 1186–1187 (2014).
35. O. R. S. John et al., Org. Lett. 9, 4009–4012 (2007).
36. J. Mendiola et al., Org. Process Res. Dev. 13, 263–267 (2009).
37. L. A. Carpino, J. Am. Chem. Soc. 82, 3133–3135 (1960).
38. M. Cherest, X. Lusinchi, Tetrahedron Lett. 30, 715–718 (1989).
39. M. Kawase, Y. Kikugawa, Chem. Pharm. Bull. (Tokyo) 29,
1615–1623 (1981).
40. W. D. Jones, Acc. Chem. Res. 36, 140–146 (2003).
41. E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 51,
3066–3072 (2012).
42. C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc.
126, 15378–15379 (2004).
43. L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic
Molecules (University Science Books, 1994), pp. 16–22.
44. C. G. Espino, J. Du Bois, Angew. Chem. Int. Ed. 40, 598–600 (2001).
ACKNOWLEDGMENTS
J.R.F. thanks NIH (grant HL034300, HL111392, DK038226) and the
Robert A. Welch Foundation (grant I-0011) for funding.
L.K. gratefully acknowledges the generous financial support of Rice
University, NIH (grant R01 GM-114609-01), NSF (CAREER:SusChEM
CHE-1455335), the Robert A. Welch Foundation (grant C-1764),
American Chemical Society Petroleum Research Fund (grant
51707-DNI1), Amgen (2014 Young Investigators’ Award to L.K.),
and Biotage (2015 Young Principal Investigator Award). A
provisional patent application (patent no. 62/360,859) has been
submitted and assigned jointly to University of Texas Southwestern
and Rice University.
SUPPLEMENTARY MATERIALS
24. R. Shrestha, P. Mukherjee, Y. Tan, Z. C. Litman, J. F. Hartwig,
J. Am. Chem. Soc. 135, 8480–8483 (2013).
25. Y. Xue et al., Eur. J. Org. Chem. 2014, 7481–7488 (2014).
26. Z. Chen et al., Org. Chem. Front. 2, 1107–1295 (2015).
27. Y. Park, K. T. Park, J. G. Kim, S. Chang, J. Am. Chem. Soc. 137,
4534–4542 (2015).
www.sciencemag.org/content/353/6304/1144/suppl/DC1
Materials and Methods
Figs. S1 to S4
Table S1
References (45–61)
28. K. Shin, H. Kim, S. Chang, Acc. Chem. Res. 48, 1040–1052 (2015).
29. F. Sun, Z. Gu, Org. Lett. 17, 2222–2225 (2015).
12 April 2016; accepted 18 August 2016
10.1126/science.aaf8713
ANTIBIOTIC RESISTANCE
Spatiotemporal microbial evolution
on antibiotic landscapes
Michael Baym,1 Tami D. Lieberman,1* Eric D. Kelsic,1 Remy Chait,1† Rotem Gross,2
Idan Yelin,2 Roy Kishony1,2,3
‡
A key aspect of bacterial survival is the ability to evolve while migrating across spatially
varying environmental challenges. Laboratory experiments, however, often study evolution in
well-mixed systems. Here, we introduce an experimental device, the microbial evolution and
growth arena (MEGA)–plate, in which bacteria spread and evolved on a large antibiotic landscape
(120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating
bacterial front. While resistance increased consistently, multiple coexisting lineages diversified
both phenotypically and genotypically. Analyzing mutants at and behind the propagating front, we
found that evolution is not always led by the most resistant mutants; highly resistant mutants
may be trapped behind more sensitive lineages.The MEGA-plate provides a versatile platform for
studying microbial adaption and directly visualizing evolutionary dynamics.
It was also instructive to compare our meth-
odology with the intermolecular Rh-catalyzed
amination procedure of Du Bois to gain a perspec-
tive on their respective complementary chemo-
selectivities (Fig. 4) (42). Both have similar efficiency
using p-ethylanisole (13), but the Du Bois procedure
leads to benzylic C-H insertion only, whereas our
methodology gives arene amination exclusively,
providing 15 and 16 in a combined 67% yield.
The influence of ligands and counterions on
the reactivity of organometallics is well prece-
dented (43, 44). However, examples of such drama-
tic bifurcation of the reaction manifold are rare
and warrant closer study to understand the ener-
getics and full synthetic potential of this metalloid-
nitrogen umpolung for direct arene aminations.
he worldwide increase in antibiotic resist-
ance has motivated numerous studies aimed
at understanding the phenotypic and geno-
typic evolution of antibiotic resistance (1–7).
These experiments have shed light on the
and multidrug environments (5, 6, 8, 9). However,
most of our current knowledge about the evolu-
tion of resistance is based on laboratory setups
with well-mixed environments (1–7, 10, 11).
In natural and clinical settings, bacteria migrate
between spatially distinct regions of selection
T
trade-offs constraining adaptive evolution in single-
SCIENCE sciencemag.org
9 SEPTEMBER 2016 • VOL 353 ISSUE 6304 1147

Dirhodium-catalyzed C-H arene amination using
hydroxylamines
Mahesh P. Paudyal, Adeniyi Michael Adebesin, Scott R. Burt,
Daniel H. Ess, Zhiwei Ma, László Kürti and John R. Falck
(September 8, 2016)
Science 353 (6304), 1144-1147. [doi: 10.1126/science.aaf8713]
Editor's Summary
This copy is for your personal, non-commercial use only.
Visit the online version of this article to access the personalization and
article tools:
http://science.sciencemag.org/content/353/6304/1144
Article Tools
Obtain information about reproducing this article:
http://www.sciencemag.org/about/permissions.dtl
Permissions
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week
in December, by the American Association for the Advancement of Science, 1200 New York
Avenue NW, Washington, DC 20005. Copyright 2016 by the American Association for the
Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.