Intermolecular Radical Mediated Anti-Markovnikov Alkene Hydroamination Using N-Hydroxyphthalimide

Article abstract of DOI:10.1021/jacs.8b06881

An intermolecular anti-Markovnikov hydroamination of alkenes has been developed using triethyl phosphite and N-hydroxyphthalimide. The process tolerates a wide range of alkenes, including vinyl ethers, silanes, and sulfides as well as electronically unbiased terminal and internal alkenes. The resultant N-alkylphthalimides can readily be transformed to the corresponding primary amines. Mechanistic probes indicate that the process is mediated via a phosphite promoted radical deoxygenation of N-hydroxyphthalimide to access phthalimidyl radicals.

Full text of DOI:10.1021/jacs.8b06881

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Communication
Intermolecular Radical Mediated Anti-Markovnikov
Alkene Hydroamination using N-Hydroxyphthalimide
Samuel William Lardy, and Valerie A. Schmidt
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Sep 2018
Downloaded from http://pubs.acs.org on September 7, 2018
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Intermolecular Radical Mediated Anti-Markovnikov Alkene Hy-
droamination using N-Hydroxyphthalimide
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Samuel W. Lardy and Valerie A. Schmidt*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
Supporting Information Placeholder
a practical solution to directly using ammonia as a sub-
strate for alkene hydroamination.
ABSTRACT: An intermolecular anti-Markovnikov hy-
droamination of alkenes has been developed using tri-
ethyl phosphite and N-hydroxyphthalimide. The process
tolerates a wide range of alkenes, including vinyl ethers,
silanes, and sulfides as well as electronically unbiased
terminal and internal alkenes. The resultant N-
alkylphthalimides can readily be transformed to the cor-
responding primary amines. Mechanistic probes indicate
that the process is mediated via a phosphite promoted
radical deoxygenation of N-hydroxyphthalimide to ac-
cess phthalimidyl radicals.
Scheme 1. PhthN• addition to unsaturations.
Nitrogen-atom functionalities are essential motifs that
appear in a wide range of pharmaceutical agents, agro-
chemicals, and natural products. The construction of C-
N bonds for use in these contexts continues to serve as a
strong motivating force for the development of new syn-
thetic methods. Olefin hydroamination has received con-
siderable attention in this area as direct addition of N-H
across a C-C double bond is a conceptually attractive
approach to alkyl amine synthesis. Many catalytic al-
kene hydroamination protocols proceed with Markovni-
kov regioselectivity1 and while examples that deliver
anti-Markovnikov regioisomers are more limited, signif-
icant advancements have been made using transition
metal2 and photoredox catalysis.3
aSee ref. 8. bSee ref. 9.
Phthalimidyl radicals7 have previously been used in
arene amination (Scheme 1A)8 and alkene aminohalo-
genation (Scheme 1B)9 by taking advantage of the pho-
tochemical lability of the N-X bonds of the PhthN• pre-
cursors. Despite the intense interest in selective C-N
bond formation via olefin hydroamination, phthalimidyl
radicals have not previously been used in this context.
This may be due to a lack of suitable precursors as the
general pathway to PhthN• is via N-X bond homolysis
where the X-group lacks transferrable H-atoms and the
addition of a stoichiometric H-atom source would likely
shunt the desired radical chain process.10
Many of these successful methods use substituted
amine substrates such that hydroamination products are
unreactive towards additional hydroamination. As a re-
sult, the use of ammonia, or practical ammonia surro-
gates as substrates while maintaining high levels of anti-
Markovnikov regioselectivity remains a largely unmet
synthetic challenge.4
N-Hydroxyphthalimide (NHPI) is an inexpensive,
commercially available reagent with long term benchtop
stability at ambient temperatures that is well known as a
precursor to PhthNO• used with great success in the
mild, aerobic oxidation of aliphatic C-H bonds.11 De-
spite the use of NHPI in radical mediated processes, its
use has been limited to that of an O-radical precursor.
We envisioned that NHPI could serve as a low-cost
source of PhthN• if a suitable deoxygenative procedure
was developed. We elected to investigate phosphites as
O-atom transfer reagents due to the wide availability of
many inexpensive phosphites and their demonstrated
We became interested in phthalimidyl radicals
(PhthN•) for use in alkene hydroamination because the
addition of N-centered radicals to alkenes would pre-
dictably deliver anti-Markovnikov adducts3a-d,5 and
phthalimide groups can be readily removed under mild
conditions to reveal primary aliphatic amines6 providing
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ability to reduce oxygen functionality.12-14 Additionally,
only, suggesting that hydroamination is indeed a radical
mediated process (entry 4).
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we envisioned that deoxygenation of NHPI would be
thermodynamically favored by the exchange of a weak
N-O bond (~55-65 kcal/mol) to form a strong phosphor-
yl unit (148 kcal/mol for OP(OEt)3).15
The relative rates of the radical process leading to 1a,
and the polar pathway leading to 1b, should be adjusta-
ble through judicious choice of reaction temperature and
radical initiator, which prompted an investigation of oth-
er commonly used thermal initiators. Benzoyl peroxide
(entry 5), and di-tert-butylperoxide (entry 6) produced
only small amounts of 1a, but dilauroyl peroxide (entry
7) resulted in nearly exclusive hydroamination of n-
butyl vinyl ether (94:6 1a:1b) producing 1a in 79% yield
at 90 °C in 20 minutes. To eliminate the undesired polar
addition leading to 1b which is likely increased at higher
reaction temperatures, we tested tert-butyl hyponitrite
which fragments at much lower temperatures compared
to AIBN, benzoyl peroxide, di-tert-butylperoxide, or
dilauroyl peroxide.16,17 Using tert-butyl hyponitrite at 35
°C resulted in clean conversion to 1a in 82% yield (entry
8). A control reaction shows that 1a is not formed in the
absence of triethyl phosphite (entry 9). This confirms the
vital role of phosphite in the radical hydroamination
process. We also found that treatment of 1a with aque-
ous hydrazine rapidly produced the corresponding pri-
mary amine 1c in 89% yield (eq 1), highlighting the role
of NHPI to serve as an ammonia surrogate in this hy-
droamination.
Table 1. n-Butyl Vinyl Ether Optimization.a
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Entry
Initiator
Solvent
Ratio
Yieldc
1a:1bb
1
2
AIBN
AIBN
PhH
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
23 : 77
93 : 7
9% + 30% 1b
67%b
3
AIBN
75 : 25
<2 : 98
38 : 62
7 : 93
79%
4
None
81% 1b
30% b
5
(BzO)2
6
(tBuO)2
8% b
7
(dodecylCO2)2
(tBuON)2
(tBuON)2
94 : 6
79%
8d
9d,e
98 : 2
82%
<2 : 98
47% 1b
aReactions carried out with NHPI (1 equiv), n-butyl vinyl
ether (5 equiv), triethyl phosphite (1.5 equiv), and radical
initiator (0.25 equiv) in the specified solvent (0.04M) at 90
b
With optimized conditions in hand, we next explored
the scope of electron-rich alkenes amenable to this regi-
oselective hydroamination process. Terminal and 1,2-
disubstituted vinyl ethers react efficiently to produce the
anti-Markovnikov hydroaminated products in good to
excellent yields (Scheme 2, compounds 2-6). Although
these reactions take place at 35 °C, we found that in-
creasing the temperature to 50 °C generally increased
the reaction efficiency for a broader range of alkenes.
The 12 hour reaction time was chosen to standardize the
protocol, although many substrates showed full con-
sumption of NHPI within 6 hours. Notably, a primary
alkyl chloride remains undisturbed under these hy-
droamination conditions (product 7). Vinyl ethers con-
taining internal alkenes were hydroaminated in lower
yields compared to α-olefin analogs, likely due to a de-
creased rate of PhthN• addition (compounds 8, 9 and
10). Vinyl sulfides and vinyl silanes were also well tol-
erated, producing the corresponding amino-sulfide and
amino-silane adducts in moderate to good yields (prod-
ucts 11-16). Also noteworthy, unlike many conventional
reductive radical transformations that require rigorous
exclusion of air or moisture, we found that oxygen re-
moval through a series of freeze-pump-thaw cycles did
not improve reaction efficiencies and reagents and sol-
vents used did not require purification beyond received
commercial grade.
°C; Bz=benzoyl. Determined by gas chromatography us-
c
ing mesitylene as an internal standard. Isolated yield of 1a
d
following purification on silica gel. Reaction temperature
35 °C. eNo triethyl phosphite added.
To test this hypothesis, we examined the hydroamina-
tion of n-butyl vinyl ether using NHPI, triethyl phos-
phite, and thermal radical initiators. We chose to begin
our investigations using n-butyl vinyl ether as a model
alkene due to its expected favorable electronic match
with the electrophilic PhthN•. As shown in Table 1, en-
try 1, a mixture of NHPI and n-butyl vinyl ether with
2,2’-azobis(2-methylpropionitrile) (AIBN) in benzene
resulted in full consumption of NHPI in 12 hours at 90
°C. Desired hydroaminated product 1a was isolated in
only 9% yield, while acetal 1b was isolated in 30%
yield. Presumably 1b formed via polar addition of the
hydroxyl group of NHPI to the electron rich vinyl ether.
Using acetonitrile (MeCN) or 1,2-dichloroethane (DCE)
as the reaction solvent (entries 2 and 3) resulted in for-
mation of desired amine 1a, with lesser amounts of 1b.
Acetonitrile led to higher selectivity for 1a (93:7 1a:1b),
while DCE afforded an overall more efficient reaction
(79% isolated yield of 1a) albeit with slightly dimin-
ished selectivity (75:25 1a:1b). A control experiment
omitting any radical initiator resulted in formation of 1b
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cleanly converted to 27 in good yield, with no evidence
of Arbuzov-type reactivity of the primary bromide with
triethyl phosphite.
Scheme 2. Hydroamination of functionalized al-
kenes.a
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4
Scheme 3. Hydroamination of unactivated alkenes.
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aAll reactions carried out using P(OEt)3 (1.5 equiv),
(tBuNO)2) (0.25 equiv), alkene (10 equiv) in DCE (0.04M)
at 50 °C for 12 h; yields are for isolated material following
chromatography on silica gel; >20:1 Regioselectivity for
b
isomer shown. Carried out using 5 equiv alkene, dilauroyl
c
peroxide (0.5 equiv) at 90 °C. Carried out using dilauroyl
peroxide (1 equiv) at 110 °C. d5 equiv alkene used.
We further investigated the viability of electronically
unbiased alkenes to undergo hydroamination (Scheme
3). Cyclohexene was successfully hydroaminated using
tert-butyl hyponitrite at 35 °C, albeit with a suboptimal
26% yield of 17 and required 24 hours to reach comple-
tion. We hypothesized that the reaction time could be
decreased and reaction efficiency improved by increas-
ing the temperature and using an alternative initiator.
Using 1 equivalent of dilauroyl peroxide at 110 °C re-
sulted in a 68% yield of 17 in only 12 hours.18 Nor-
bornene and other cyclic alkenes such as cyclopentene,
cycloheptene, and cyclooctene all readily underwent
efficient hydroamination using these conditions (prod-
ucts 18-21). In the case of 1-methylcyclohexene where
regioisomeric products are possible, hydroamination
proceeded with exclusive anti-Markovnikov selectivity
and moderate 80:20 diastereoselectivity favoring the
trans-1,2-disubstituted cyclohexane adduct 22. Exo-
aAll reactions carried out with P(OEt)3 (1.5 equiv), speci-
fied initiator (0.25 equiv), alkene (10 equiv) in DCE
(0.04M) at the specified temperature for 12 h; yields shown
were determined by gas chromatography using mesitylene
b
as an internal standard. Carried out using dilauroyl perox-
ide (1 equiv) at 110 °C for 12 h; yields are for isolated ma-
terial following chromatography on silica gel; >20:1 Regi-
c
oselectivity for isomer shown. Carried out using (tBuON)2
d
methylene
containing
1-isopropyl-4-
(0.25 equiv) at 50 °C for 12 h. Carried out using dilauroyl
methylenecyclohexane and camphene were both hy-
droaminated successfully to produce 23 and 24, respec-
tively, in good yields. The bicyclic camphene product 24
was formed as a single diastereoisomer while the less
bulky 23 was formed as a 83:17 trans:cis mixture. Elec-
tronically unbiased terminal alkenes, tert-butyl ethylene
and 1-hexene, also underwent efficient anti-
Markovnikov selective hydroamination (products 25 and
26). Primary bromide containing 5-bromo-1-pentene
peroxide (0.20 equiv).
5-Hexenyl pivalate was converted to 28 in 54% yield
as a single regioisomer. Acyclic and unactivated trans-4-
octene and 3-methylbut-3-enyl pivalate were both clean-
ly hydroaminated to produce 29 and 30 in good yields.
Diallyl ether was transformed to 31, inserting a 5-exo-
trig cyclization during the hydroamination process. Hy-
droamination of only one alkene of diallyl ether without
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cyclization was not detected suggesting that the rate of
Page 4 of 7
To demonstrate the scalability and practicality of our
intermolecular anti-Markovnikov alkene hydroamina-
tion, we carried out the hydroamination of norbornene
on a 1.0 g scale of NHPI (Scheme 5A). We found no
significant decrease in reaction efficiency at this scale,
affording 18 in 80% yield in 12 hours. As anticipated,
the removal of the phthalimido group was easily
achieved using a small excess of aqueous hydrazine in
methanol at 60 °C for 30 minutes to deliver 2-
aminonorbornane in 95% yield (Scheme 5B).
cyclization (~9x106 s-1)19 is faster than terminal H-atom
transfer. We also investigated 1,5-cis-cis-cyclooctadiene
as an additional substrate capable of cyclization during
the hydroamination process. We found that a mixture of
bicyclic hydroaminated product 32a and monocyclic
hydroaminated product 32b were formed in a 1.5:1 ratio
(21% yield 32a, 14% yield 32b). This product mixture
suggests that the slower 5-exo-trig cyclization rate
(~1x105 s-1)19 of this substrate is competitive with prod-
uct forming H-atom abstraction. The hydroamination of
1-octyne resulted in the formation of the corresponding
substituted N-vinyl phthalimide 33 in moderate yield
exclusively as the E isomer.
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Scheme 5. Hydroamination scale-up and phthalimide
deprotection.
A plausible mechanism for this hydroamination is out-
lined in Scheme 4. Thermal radical initiation is followed
by H-atom abstraction from NHPI to produce PhthNO•
which then undergoes reversible addition to triethyl
phosphite.13d The PhthNO-phosphite adduct can then
undergo β-scission of the relatively weak N-O bond to
form triethyl phosphate and PhthN• which adds to the
alkene to preferentially produce the more substituted C-
centered radical. This alkene addition product is now
poised to perform a thermodynamically favorable H-
atom abstraction from another equivalent of NHPI (2°
C-H bond formed ~93-98 kcal/mol15 versus 88 kcal/mol
O-H bond broken20) to afford the hydroaminated product
and regenerate PhthNO•. Formally, NHPI supplies both
the required N- and H-atoms for alkene hydroamination.
a5 equiv alkene used.
In conclusion, we describe an anti-Markovnikov selec-
tive hydroamination of a variety of alkene substrates
achieved via a phosphite promoted O-atom transfer pro-
cess. This work uses inexpensive reagents, triethyl
phosphite and NHPI, to access PhthN•.21 Our anti-
Markovnikov hydroamination method addresses limita-
tions of prior work generating PhthN• as it excludes fur-
ther functionalization of NHPI, negates the use of UV
irradiation, and circumvents expensive photocatalysts.
The direct introduction of a phthalimido group is partic-
ularly attractive as simple deprotection procedures can
be used to reveal versatile primary amines.
Scheme 4. Hydroamination mechanistic proposal.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental details; characterization data including NMR
spectra of novel compounds; methods and results (PDF)
AUTHOR INFORMATION
Corresponding Author
a10 equiv alkene used.
*vschmidt@ucsd.edu
To support this mechanistic hypothesis, we prepared
NHPI-d1 and subjected it to an excess of tert-butyl eth-
ylene and 10 mol % tert-butyl hyponitrite at 50 °C for
12 hours. Product 25-d1 was isolated in 58% yield with
deuterium incorporation exclusively at the C-2 position
adjacent to the phthalimido group, consistent with the
proposed mechanism.
ORCID
Valerie A. Schmidt: 0000-0001-9647-6756
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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Journal of the American Chemical Society
(7) (a) Lüning, U.; Skell, P. S. Tetrahedron 1985, 41, 4289 – 4302.
This work was supported by start-up funds provided by the
University of California San Diego.
DOI: 10.1016/S0040-4020(01)97200-X; (b) Day, J. C.; Go-
vindaraj, N.; McBain, D. S.; Skell, P. S.; Tanko, J. M. J. Org.
Chem. 1986, 51, 4959 – 4963. DOI: 10.1021/jo00375a038
(8) (a) Kim, H.; Kim, T.; Lee, D. G.; Roh, S. W.; Lee, C. Chem.
Commun. 2014, 50, 9273 – 9276. DOI: 10.1039/C4CC03905J;
(b) Allen, L. J.; Carera, P. J.; Lee, M.; Sanford, M. S. J. Am.
Chem. Soc. 2014, 136, 5607 – 5610. DOI: 10.1021/ja501906x
(9) (a) Day, J. C.; Katsaros, M. G.; Kocher, W. D.; Scott, A. E.;
Skell, P. S. J. Am. Chem. Soc. 1978, 100, 1950 – 1951. DOI:
10.1021/ja00474a063; (b) Kirsch, A.; Lüning, U. J. prakt. Chem.
1998, 340, 129 – 134. DOI: 10.1002/prac.19983400205; (c)
Lüning, U.; Kirsch, A. Chem. Ber. 1993, 126, 1171 – 1178.
DOI: 10.1002/cber.19931260517
1
2
3
4
5
6
7
8
REFERENCES
(1) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675 – 703.
DOI: 10.1021/cr960433d; (b) Hong, S.; Marks, T. J. Acc. Chem.
Res. 2004, 37, 673 – 696. DOI: 10.1021/ar040051r; (c) Muller,
T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem.
Rev. 2008, 108, 3795 – 3892. DOI: 10.1021/cr0306788; (d)
Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J.
Chem. Rev. 2015, 115, 2596 – 2697. DOI: 10.1021/cr300389u;
(e) Coman, S. M.; Parvulescu, V. I. Org. Process Res. Dev.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) For additional examples of hydroxylamine derivatives used as
aminating reagents, see: (a) Davies, J.; Morcillo, S. P.; Douglas,
J. J.; Leonori, D. Chem. Eur. J. 2018, 24, 12154 – 12163. DOI:
10.1002/chem.201801655.; (b) Hemric, B. N.; Shen, K.; Wang,
2015, 19, 1327 – 1355. DOI: 10.1021/acs.oprd.5b00010
(2) (a) Ickes, A. R.; Ensign, S. C.; Gupta, A. K.; Hull, K. L. J. Am.
Chem. Soc. 2014, 136, 11256 11259. DOI:
ꢀ
–
10.1021/ja505794u; (b) Ensign, S. C.; Vanable, E. P.; Kortman,
G. D.; Weir, L. J.; Hull, K. L. J. Am. Chem. Soc. 2015, 137,
13748 – 13751. DOI: 10.1021/jacs.5b08500; (c) Utsunomiya,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702 – 2703.
DOI: 10.1021/ja031542u; (d) Munro-Leighton, C.; Blue, E. D.;
Gunnoe, T. B. J. Am. Chem. Soc. 2006, 128, 1446 – 1447. DOI:
10.1021/ja057622a; (e) Miki, Y.; Hirano, K.; Satoh, T.; Miura,
M. Angew. Chem. Int. Ed. 2013, 52, 10830 – 10834. DOI:
10.1002/anie.201304365; (f) Miki, Y.; Hirano, K.; Satoh, T.;
Q. J. Am. Chem. Soc. 2016, 138, 5813
10.1021/jacs.6b02840.; (c) Ma, Z.; Zhou, Z.; Kürti, L. Angew.
Chem. Int. Ed. 2017, 56, 9886 9890. DOI:
– 5816. DOI:
–
10.1002/anie.201705530.; (d) Jat, J. L.; Paudyal, M. P.; Gao, H.;
Xu, Q.-L.; Yousufuddin, M.; Devarajan, D.; Ess, D. H.; Kürti,
L.; Falck, J. R. Science, 2014, 343, 61
– 65. DOI:
10.1126/science.1245727.; (e) Zhu, C.; Li, G.; Ess, D. H.; Falck,
J. R.; Kürti, L. J. Am. Chem. Soc. 2012, 134, 18253 – 18256.
DOI: 10.1021/ja309637r.; (f) Paudyal, M. P.; Adebesin, A. M.;
Burt, S. R.; Ess, D. H.; Ma, Z.; Kürti, L.; Falck, J. R. Science,
2016, 353, 1144 – 1147. DOI: 10.1126/science.aaf8713.; (g)
Shuler, S. A.; Yin, G.; Krause, S. B.; Vesper, C. M.; Watson, D.
A. J. Am. Chem. Soc., 2016, 138, 13830 – 13833. DOI:
10.1021/jacs.6b08932.; (h) Ortiz, Jr. G. X.; Hemric, B. N.;
Miura, M. Org. Lett. 2014, 16, 1498
– 1501. DOI:
10.1021/ol5003219; (g) Zhu, S.; Miljianskul, N.; Buchwald, S.
L. J. Am. Chem. Soc. 2013, 135, 15746 – 15749. DOI:
10.1021/ja4092819; (h) Pirnot, M. T.; Wang, Y.-M.; Buchwald,
S. L. Angew. Chem. Int. Ed. 2016, 55, 48 – 57. DOI:
10.1002/anie.201507594; (i) Yang, Y.; Shi, S.-L.; Niu, D.; Liu,
P.; Buchwald, S. L. Science 2015, 349, 62 – 66. DOI:
10.1126/science.aab3753.
Wang, Q. Org. Lett. 2017, 19, 1314
– 1317. DOI:
10.1021/acs.orglett.7b00358.; (i) Hendrick, C. E.; Bitting, K. J.;
Cho, S.; Wang, Q. J. Am. Chem. Soc. 2017, 139, 11622 – 11628.
DOI: 10.1021/jacs.7b07661.; (j) Kattamuri, P. V.; Yin, J.;
Siriwongsup, S.; Kwon, D.-H.; Ess, D. H.; Li, Q.; Li, G.; Yousu-
fuddin, M.; Richardson, P. F.; Sutton, S. C.; Kürti, L. J. Am.
(3) (a) Musacchio, A. J.; Nguyen, L. Q.; Beard, H.; Knowles, R. R.
J. Am. Chem. Soc. 2014, 136, 12217
– 12220. DOI:
10.1021/ja5056774; (b) Miller, D. C.; Choi, G. C.; Orbe, H. S.;
Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 13492 – 13495.
DOI: 10.1021/jacs.5b09671; (c) Musacchio, A. J.; Lainhart, B.
C.; Zhang, X.; Naguib, S. G.; Sherwood, T. C.; Knowles, R. R.
Science 2017, 355, 727 – 730. DOI: 10.1126/science.aal3010.;
(d) Zhu, Q.; Graff, D. E.; Knowles, R. R. J. Am. Chem. Soc.
2018, 140, 741 – 747. DOI: 10.1021/jacs.7b11144.; For organo-
photoredox hydroaminations, see: (e) Nguyen, T. M.; Nicewicz,
D. A. J. Am. Chem. Soc. 2013, 135, 9588 – 9591. DOI:
10.1021/ja4031616; (f) Nguyen, T. M.; Manohar, N.; Nicewicz,
D. A. Angew. Chem. Int. Ed. 2014, 53, 6198 – 6201. DOI:
10.1002/anie.201402443.
Chem. Soc. 2017, 139, 11184
–
11196. DOI:
10.1021/jacs.7b05279.; (k) Zhou, Z.; Ma, Z.; Behnke, N. E.;
Gao, H.; Kürti, L. J. Am. Chem. Soc. 2017, 139, 115 – 118. DOI:
10.1021/jacs.6b12712.; (l) Hongyin, G.; Zhou, Z.; Kwon, D.-H.;
Coombs, J.; Jones, S.; Behnke, N. E.; Ess, D. H.; Kürti, L. Na-
ture Chem. 2017, 9, 681 – 688. DOI: 10.1038/NCHEM.2672.;
(m) Xu, F.; Shuler, S. A.; Watson, D. A. Angew. Chem. Int. Ed.,
2018, 57, 12081 – 12085. DOI: 10.1002/anie.201806295.; And
references 2e-i.
(11) (a) Recupero, F.; Punta, C. Chem. Rev. 2007, 107, 3800 – 3842.
DOI: 10.1021/cr040170k; (b) Coseri, S. Catal. Rev. 2009, 51,
218 – 292. DOI: 10.1080/01614940902743841.; (c) Nutting, J.
E.; Rafiee, M.; Stahl, S. S. Chem. Rev. 2018, 118, 4834 – 4885.
DOI: 10.1021/acs.chemrev.7b00763.
(12) For leading examples of peroxide, hydroperoxide, and epoxide
deoxygenation using phosphites, see: (a) Kharasch, M. S.;
Mosher, R. A.; Bengelsdorf, I. S. J. Org. Chem. 1960, 25, 1000
– 1006. DOI: 10.1021/jo01076a035; (b) Gardner, J. N.; Carlon,
F. E.; Gnoj, O. J. Org. Chem. 1968, 33, 3294 – 3297. DOI:
10.1021/jo01272a055; (c) Burn, A. J.; Cadogan, J. I. G.; Bun-
(4) For a recent review of catalytic reactions using ammonia, see:
(a) Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem. Int. Ed.
2011, 50, 86 – 95. DOI: 10.1002/anie.201002354.; For ammonia
hydroamination of alkynes and allenes, see: (b) Lavallo, V.;
Frey, G. D.; Donnadieu, B.; Soleilhavoup, M.; Bertrand, G. An-
gew. Chem. Int. Ed. 2008, 47, 5224
– 5228. DOI:
10.1002/anie.200801136.; For a formal ammonia Markovnikov
selective alkene hydroamination, see: (c) Yang, Y.; Wong, N. I.;
Teo, P. Eur. J. Org. Chem. 2015, 1207
– 1210. DOI:
10.1002/ejoc.201403654.
yan, P. J. J. Chem. Soc. 1963, 1527
– 1533. DOI:
(5) (a) Guin, J.; Muck-Lichtenfeld, C.; Grimme, S.; Studer, A. J.
Am. Chem. Soc. 2007, 129, 4498 4503. DOI:
10.1039/JR9630001527; (d) Scott, C. J. Org. Chem. 1957, 22,
1118 – 1119. DOI: 10.1021/jo01360a613; For nitro group deox-
ygenation using phosphites, see: (e) Cadogan, J. I. G. Synthesis
1969, 1969, 11 – 17. DOI: 10.1055/s-1969-34189.
–
10.1021/ja0692581; (b) Kärkäs, M. D. ACS Catal. 2017, 7, 4999
– 5022. DOI: 10.1021/acscatal.7b01385; (c) Hofmann, A. W.
Ber. Dtsch. Chem. Ges. 1883, 16, 558
– 560. DOI:
(13) For nitroxyl radical deoxygenation, see: (a) Cadogan, J. I. G.;
Rowley, A. G. J. Chem. Soc. Perkin Trans. 2, 1974, 1030 –
1033. DOI: 10.1039/P29740001030; (b) Berti, C.; Greci, L. J.
Org. Chem. 1981, 46, 3060 – 3063. DOI: 10.1021/jo00328a014.;
(c) Mar’in, A.; Damiani, E.; Canestrari, S.; Dubs, P.; Greci, L. J.
Chem. Soc. Perkin Trans. 2 1999, 1363 – 1367.; For deoxygena-
tion of alkoxy and alkylperoxy radicals, see: (d) Walling, C.;
Rabinowitz, R. J. Am. Chem. Soc. 1959, 81, 1243 – 1249. DOI:
10.1002/cber.188301601120; (d) Löffler, K.; Freytag, C. Ber.
Dtsch. Chem. Ges. 1909, 42, 3427
–
3431. DOI:
10.1002/cber.19090420377.
(6) Wuts, P. G. M. and Greene, T. W. Greene’s Protective Groups
in Organic Synthesis, 4th ed.; Wiley: Hoboken, 2007; pp 790 –
793.
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Page 6 of 7
10.1021/ja01514a.; (e) Schwetlick, K.; Pionteck, J.; Winkler, A.;
royl peroxide has a 10 h half-life at 62 °C, see: (b) Charrier, N.
(2007). Dilauroyl Peroxide. In Encyclopedia of Reagents for Or-
ganic Synthesis, (Ed.). DOI: 10.1002/9780470842898.rn00698
(17) tert-Butyl hyponitrite has a 7 h half-life at 45 °C, see: Boukou-
valas, J., Cren, S. and Renaud, P. (2007). Di‐t‐butyl Hyponitrite.
In Encyclopedia of Reagents for Organic Synthesis, (Ed.). DOI:
10.1002/047084289X.rd062.pub2
(18) For additional optimization for the hydroamination of cyclohex-
ene, see Table S2 in the Supporting Information.
(19) Newcomb, M. Radicals in Organic Synthesis; Wiley-VCH Ver-
lag Gmbh: Weinheim, Germany, 2001; pp 327 – 329.
Hähner, U.; Kroschwitz, H.; Habicher, W. D. Polym. Degrad.
Stab. 1991, 31, 219 – 228. DOI: 10.1016/0141-3910(91)90077-
5.
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(14) For radical deoxygenations of preformed or in situ formed phos-
phites, see: (a) Zhang, L.; Koreeda, M. J. Am. Chem. Soc. 2004,
126, 13190 – 13191. DOI: 10.1021/ja0462777.; (b) Jordan, P.
A.; Miller, S. J. Angew. Chem. Int. Ed. 2012, 51, 2907 – 2911.
DOI: 10.1002/anie.20110933.; (c) Shono, T.; Matsumura, Y.;
Tsubata, K.; Sugihara, Y. J. Org. Chem. 1979, 44, 4508 – 4511.
DOI: 10.1021/ji00393a010.; (d) Lam, K.; Markó, I. E. Org. Lett.
2011, 13, 406 – 409. DOI: 10.1021/OL102714s.
(15) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds, CRC Press: Boca Raton, 2003.
(16) Benzoyl peroxide has a 10 h half-life at ~80 °C and AIBN has a
10 h half-life at ~70 °C, see: (a) Walling, C. Tetrahedron 1985,
41, 3887 – 3900. DOI: 10.1016/S0040-4020(01)97172-8. Dilau-
9
(20) Warren, J. J.; Tronic, T. A.; Mayer, J. M. Chem. Rev. 2010, 110,
6961 –7001. DOI: 10.1021/cr100085k
(21) P(OEt)3 can be purchased from Sigma Aldrich for $0.04/g and
NHPI can be purchased from Acros Organics for $0.17/g. Prices
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