Design of modified amine transfer reagents allows the synthesis of α-chiral secondary amines via CuH-catalyzed hydroamination

Article abstract of DOI:10.1021/jacs.5b05446

The CuH-catalyzed hydroamination of alkenes and alkynes using a silane and an amine transfer reagent represents a simple strategy to access chiral amine products. We have recently reported methods to prepare chiral amines with high efficiency and stereoselectivity using this approach. However, the current technology is limited to the synthesis of trialkylamines from dialkylamine transfer reagents (R₂NOBz). When monoalkylamine transfer reagents [RN(H)OBz] were used for the synthesis of chiral secondary amines, competitive, nonproductive consumption of these reagents by the CuH species resulted in poor yields. In this paper, we report the design of a modified type of amine transfer reagent that addresses this limitation. This effort has enabled us to develop a CuH-catalyzed synthesis of chiral secondary amines using a variety of amine coupling partners, including those derived from amino acid esters, carbohydrates, and steroids. Mechanistic investigations indicated that the modified amine transfer reagents are less susceptible to direct reaction with CuH.

Full text of DOI:10.1021/jacs.5b05446

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Article
The Design of Modified Amine Transfer Reagents Allows the Synthesis
of #-Chiral Secondary Amines via CuH-Catalyzed Hydroamination
Dawen Niu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Jul 2015
Downloaded from http://pubs.acs.org on July 6, 2015
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The Design of Modified Amine Transfer Reagents Allows the
Synthesis of α-Chiral Secondary Amines via CuH-Catalyzed
Hydroamination
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Dawen Niu and Stephen L. Buchwald*
Department of Chemistry, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139
S Supporting Information
ABSTRACT: The CuHꢀcatalyzed hydroamination of alkenes and alkynes using a silane and an amine transfer reagent
represents a simple strategy to access chiral amine products. We have recently reported methods to prepare chiral
amines with high efficiency and stereoselectivity using this approach. However, the current technology is limited to the
synthesis of trialkylamines from dialkylamine transfer reagents (R2NOBz). When monoalkylamine transfer reagents
[RN(H)OBz] were used for the synthesis of chiral secondary amines, competitive, nonproductive consumption of these
reagents by the CuH species resulted in poor yields. In this paper, we report the design of a modified type of amine
transfer reagents that addresses this limitation. This effort has enabled us to develop a CuHꢀcatalyzed synthesis of
chiral secondary amines using a variety of amine coupling partners, including those derived from amino acid esters,
carbohydrates, and steroids. Mechanistic investigations indicated that the modified amine transfer reagents are less
susceptible to direct reaction with CuH.
Introduction Chiral amines are ubiquitous structural motifs found in many pharmaceutical agents, natural products,
and catalysts for asymmetric synthesis (see Figure 1 for selected examples). As a result, general and selective methods
for their synthesis have long been pursued. 1 Methodologies using resolution 2 or chiral auxiliaries 3 have been
established as reliable ways to procure these compounds. Significant progress has also been made in the development
of catalytic, asymmetric methods for their preparation. Many of these reported catalytic methods are based on
asymmetric transformations of imine, enamine, or enamide intermediates.4 Other strategies, such as asymmetric
allylation of amine nucleophiles5 and direct C–H bond insertion by a nitrenoid species,6 are important alternatives.
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Figure 1. Representative natural products and pharmaceutical agents that feature a chiral amine motif.
Asymmetric hydroamination,7 the net stereoselective addition of a hydrogen atom and an amino group directly
across a double bond, represents a particularly appealing strategy to prepare chiral amines. Typically, a hydroamination
reaction entails the direct union of an alkene 1 with a primary or secondary amine nucleophile 2 in the presence of a
catalyst (Figure 2a).7 Based on catalytic copper(I) hydride chemistry8 and recent developments in the copperꢀmediated
amination of carbonꢀbased nucleophiles,9 our group recently reported a mechanistically distinct approach towards
asymmetric hydroamination10 (Figure 2b). In this technique, an olefin first undergoes asymmetric hydrocupration to
provide an alkylcopper intermediate, which is then intercepted by a suitable electrophilic amine transfer reagent. Our
laboratory has applied this hydroamination strategy to the synthesis of chiral tertiary alkylamines from styrenes,10a 1,1ꢀ
disubstituted alkenes,10b vinylsilanes,10c and alkynes.10d Independently, Miura and coworkers have reported a similar
approach for the hydroamination of styrenes11a and strained internal alkenes.11b
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Figure 2. Hydroamination approaches to make αꢀchiral amines.
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To date, this approach to hydroamination10,11 has been limited to the synthesis of tertiary alkylamines with Oꢀ
benzoyl-N,Nꢀdialkylhydroxylamines (R2NOBz, R = alkyl) as the dialkylamine transfer reagents. The expansion of this
method to monoalkylamine transfer reagents to allow the direct preparation of chiral secondary amines would be of
considerable interest. Herein we report the development of a copperꢀcatalyzed hydroamination process to directly
generate chiral, branched secondary amines 8 from styrenes (Figure 2c). One key factor in the development of this
method is the design and use of a modified class of amine transfer reagents 7, which improved the efficiency and
generality of the transformation. Mechanistic studies indicate that use of the modified amine transfer reagent
suppresses nonproductive consumption of the reagent by the copper hydride intermediate.
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Results and Discussion
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We began our work by studying the reaction between styrene (9a) and OꢀbenzoylꢀNꢀbenzylhydroxylamine12
[BnN(H)OBz, 10a] utilizing our previously reported conditions10,13 (Figure 3a). It was found that the desired secondary
amine 11a was produced in moderate yield (60%) and excellent enantioselectivity. This result suggested the
compatibility between the copper hydride and alkylcopper species with the N–H bond contained in both the amine
transfer reagent 10a and the secondary amine product 11a. However, we found that this transformation had a limited
substrate scope: either orthoꢀ or βꢀsubstitution on the styrene substrate led to a dramatic drop in reaction efficiency
(11b and 11c, 25% and <10% yield, respectively). We reasoned that the poor yields of 11b and 11c might be caused by
the more challenging hydrocupration of the substituted styrenes (9b and 9c). In these cases, the (relatively rapid)
nonproductive consumption of amine transfer reagent 10a by LCuꢀH (Figure 3b, red arrow) would diminish the overall
yields of the respective secondary amine products.
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a) Hydroamination of styrenes 9a-c using BnNHOBz (10a)a
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Cu(OAc)2 (2.0 mol%)
Bn
R2
O
NH R2
H
N
(R)-L (2.2 mol%), PPh3 (4.4 mol%)
R1
R1
O
+
Bn
O
O
O
HSi(OEt)2Me (2.0 equiv)
THF (0.5 M), 40 °C, 16 h
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PAr2
PAr2
9a-c
Bn
10a (1.2 equiv)
11a–c
O
Bn
Bn
NH
NH Me
NH
9
L = DTBM-SEGPHOS
Me
Me
Me
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Ar = 3,5-(tBu)2-4-MeO-C6H2
11a
60% yield, 96% ee
11b
25% yield
11c
< 10% yield
b) Mechanistic rationale
c) Hydroaminationa of 9b and 9c using modified amine transfer reagents 10a–e
CuL R2
R1
9a-c
yield of 11b
90%
12a–c
Productive pathway
yield of 11c
O
H
BnNHOBz
60%
Non-productive pathway
N
Bn
O
10a
LCu-H
R
BnNHOBz
5
30%
10a
10a–e
OEt
11a–c
Me Si OBz
OEt
H
EtO Si OEt
Me
R =
H
(10a)
4-CF3
(10b)
4-NMe2
(10e)
2-MeO 4-MeO
(10c)
LCu–OBz
(10d)
d) Scope of different styrenes in hydroamination reactions using 10e (1.2 equiv)b
Bn
Bn
Bn
Bn
Bn
Bn
NH
NH
NH
NH
NH
NH
Me
BnO
Me
Me
EtO2C
Me
Me
11a, 93% yield, 97% ee 11b, 84% yield, 94% ee 11cc, 89% yield, 96% ee 11d, 73% yield, 95% ee 11e, 88% yield, 96% ee
OMe
11fc
yield ee
1 mmol 85% 95%
5 mmol 87% 95%
Bn
Bn
Bn
Bn
Bn
Bn
NH
NH
NH
NH
NH
NH
N
O
Me
Me
Me
Me
Me
Me
Me
Br
N
N
F
CF3
11g, 86% yield, 92% ee
yield ee
11l ortho- 90% 92%
11mmeta- 89% 94%
11n para- 92% 96%
SO2Ph
11h, 74% yield, 99% ee
11i, 82% yield, 97% ee 11j, 83% yield, 98% ee 11k, 92% yield, 95% ee
Figure 3. CuHꢀcatalyzed hydroamination of styrenes for the formation of chiral secondary amines. a Yields are
determined using GC with dodecane as an internal standard; unless otherwise noted, CuH solution used in this study
was prepared in a nitrogenꢀfilled glovebox. b Isolated yields on 1 mmol scale (average of two runs); enantiomeric
excesses (ee) were determined by chiral HPLC analysis; see Supporting Information for experimental details. c Three
equivalents of HSi(OEt)2Me was used, and 10e was added over 1.5 hours.
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We postulated that the use of an amine transfer reagent that is less susceptible to direct reaction with LCuꢀH 5
would change the relative rates of the desired (hydrocupration) versus the undesired [BnN(H)OBz decomposition]
pathway, thus expanding the substrate scope for the synthesis of secondary amines. We hypothesized that perturbation
of the electronic properties of the benzoyl group of electrophilic amine source 10 might lead to such an effect.14 Thus,
we prepared amine transfer reagents 10b–e (Figure 3c) by coupling commercially available Nꢀbenzyl hydroxylamine
hydrochloride with various carboxylic acids, and tested these new amine transfer reagents for the hydroamination of
styrenes 9b and 9c under the same conditions as depicted in Figure 3a. As summarized in Figure 3c, we found the use
of more electronꢀrich amine transfer reagents 10c–e was beneficial to the reaction efficiency. Specifically, the use of
10e, an amine transfer reagent bearing a 4ꢀ(dimethylamino)benzoate group, provided the highest yields of 11b and 11c.
In contrast, 10b, bearing the electronꢀdeficient 4ꢀ(trifluoromethyl)benzoate group, gave poorer yields than the parent
benzoate 10a.15
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With 4ꢀ(dimethylamino)benzoate 10e as the amine transfer reagent, we found that a variety of styrene derivatives
could be converted to the corresponding chiral secondary amines in good to excellent yield and with excellent
enantioselectivity (Figure 3d). All these reactions proceeded to completion within 5 hours at 40 °C or 16 hours at room
temperature under the reaction conditions shown in Figure 3a. For example, βꢀsubstituted styrenes and styrenes with
orthoꢀsubstitution are suitable substrates (11b–e).16 Additionally, styrenes bearing both electronꢀdonating and electronꢀ
withdrawing substituents are tolerated as well (11f–g), and the reaction efficiency is not reduced when performed on a
5 mmol scale (11f). Further, styrenes containing heterocyclic rings are effective reaction partners (11h–j). Use of 4ꢀ
fluorostyrene yielded 11k, which resembles the core structure of PFꢀ05105679 (Figure 1), in 92% yield and 95% ee.
Lastly, this process also permits the preparation of 11l–n, which contain synthetically versatile aryl bromide. The
successful formation of 11l was somewhat surprising, since related alkylcopper intermediates had been shown to
undergo rearrangement to afford the arylcopper species.17
We next investigated the scope of the amine transfer reagents that could be employed (Table 1). The amine transfer
agents used in this study were prepared from the corresponding primary hydroxylamine 15 and 4ꢀ
(dimethylamino)benzoic acid via condensation effected by 1,1’ꢀcarbonyldiimidazole (CDI).18 As summarized in Table
1, amine transfer reagents with secondary or tertiary alkyl group substituents are competent substrates, delivering
products 17a–d in high yields and enantioselectivities. The use of chiral amine transfer agents afforded products with
high level of diastereoselectivity. The configuration of the newly generated stereocenter was determined by ligand
employed (17c and 17d). When either racemic ligand or racemic electrophile was used, a near unity ratio of
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diastereomers was formed (see Supporting Information). These results are consistent with the diastereoselectivity of
the hydroamination process being under catalyst control.
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Table 1. Scope of amine transfer reagents in hydroamination reactions.
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Reactions performed on 1 mmol scale for 17a–d and 0.5 mmol scale for 17e–l. Isolated yields are reported (average of
two runs). Enantiomeric excesses (ee) were determined by chiral HPLC analysis or 1H NMR analysis. Diastereomeric
ratios (dr) were determined by 1H NMR or gas chromatography analysis. a Toluene was used as the solvent, and amine
transfer reagent with a pivolate leaving group was used as the substrate (see Supporting Information).
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We found that amine transfer reagents prepared from αꢀamino esters19 were competent substrates as well, and gave
the Nꢀmonoalkylated amino esters with high levels of stereocontrol (17e–l, Table 1). Amino esters spanning a range of
steric and electronic properties could be utilized (17e–j). Importantly, the protecting groups on the amino esters could
be methyl (17e–f and 17j), benzyl (17g), or tertꢀbutyl (17h–i), allowing a variety of choices for the selection of
downstream deprotection methods. No epimerization of the labile stereocenter adjacent to the carbonyl group was
observed, reflecting the overall mildness of the reaction system. Not surprisingly, use of different enantiomers of the
ligand led to the formation of different diastereomers (17h and 17i), again supporting a catalystꢀcontrolled
stereodetermining step. Furthermore, an amine transfer reagent derived from a quaternary αꢀamino ester could also be
employed, giving 17j in excellent yield and enantioselectivity. This method could also transform a vinylsilane10c to the
αꢀaminosilane (17k), a class of building blocks often employed for the synthesis of peptidomimetics.20 Finally, this
hydroamination reaction can be integrated into a cascade sequence, delivering cyclic product 17l after in situ alkylation
of the intermediate secondary amine.
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To further demonstrate the utility of this methodology, we applied it in the context of drug molecule synthesis
(Scheme 1). For example, this method was applied to the synthesis of Sensipar (21), a drug used to treat secondary
hyperparathyroidism. Commercially available aldehyde 18 was converted to amine transfer reagent 19 and then
subjected to hydroamination conditions in the presence of 1ꢀvinylnaphthalene (20) to give Sensipar (21) in 81% yield
and 89% ee (Scheme 1a). This methodology was also applied to the derivatization of commercial pharmaceuticals. For
instance, chlorpromazine (22), an antipsychotic, could be converted to vinylarene 23,21 which then underwent
hydroamination with Lꢀvaline derived amine transfer reagent 24, to yield 25 (Scheme 1b). In a similar fashion,
loratadine (26), an antiꢀhistamine drug, could be converted to 27, and then coupled with 29, an amine transfer reagent
derived from an estrone derivative 28, to afford the conjugated product 30 in 85% yield and > 20:1 dr (Scheme 1c).
Lastly, vinylarene 32 made from tufnil (31), a nonꢀsteroid antiꢀinflammatory drug, could successfully couple with 34,
an amine transfer reagent prepared from a glucose derivative 33, to afford 35 in 73% yield and 17:1 dr (Scheme 1d).
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Scheme 1. Hydroamination reaction in the synthesis and derivatization of drugs.
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Reactions performed on 0.5 mmol scale. Isolated yields are reported (average of two runs). Enantioselectivities and
diastereoselectivities were determined by chiral HPLC or 1H NMR analysis. Conditions A: 1) NH2OH•HCl, pyridine;
2) NaBH3CN, HCl in MeOH, MeOH/THF; 3) 4ꢀ(dimethylamino)benzoic acid, CDI, CH2Cl2. Conditions B: Pd(OAc)2,
SPhos, potassium vinyltrifluoroborate, K2CO3, dioxane/H2O.
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Mechanistic Studies
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Competition experiments were performed to investigate the role of the modified amine transfer reagents used in this
study. We had hypothesized that the narrow substrate scope of the CuHꢀcatalyzed hydroamination reaction using
monoalkylamine transfer agents [e.g., BnN(H)OBz] was due to the susceptibility of these reagents toward direct, nonꢀ
productive reduction by LCuH. To address this, we conducted a competition experiment by exposing a 1:1 mixture of a
pair of monoꢀ and dialkylamine transfer reagents, 10a and 36, to HSi(OEt)2Me and copper catalyst in d8ꢀTHF in the
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absence of styrene, and monitored the consumption of these two reagents by H NMR spectroscopy (Figure 4a). We
found that LCuH was capable of directly reacting with the amine transfer reagents, and over 80% of the
monoalkylamine transfer agent 10a was consumed within one hour, to give BnNH2 and the corresponding silylated
benzoyl ester (37).22 In contrast, only a trace (< 5%) of the dialkylamine transfer agent 36 was consumed during the
same period of time.23 We then subjected a 1:1 mixture of a pair of monoalkylamine transfer reagents, 10a (parent
benzoate) and 10e [4ꢀ(dimethylamino)benzoate], to identical conditions as described above (Figure 4b). In this case,
both 10a and 10e were gradually consumed in the reaction system, giving the corresponding silylated esters (37 and
38) as products. Importantly, we found that the modified amine transfer reagent 10e was consumed at a considerably
slower rate than was 10a. The higher stability of the modified monoalkylamine transfer reagents toward direct reaction
with LCuH reaction is consistent with the increased substrate scope seen using the 4ꢀ(dimethylamino)benzoateꢀderived
amine transfer reagents.
b)
a)
N(H)Bn
O
N(H)Bn
O
Si*
O
Si*
O
N(H)Bn
NBn2
Si*
O
O
O
O
O
O
O
O
O
O
Conditions A
Conditions A
+
+
+
d8-THF, 40 °C
d8-THF, 40 °C
H
NMe2
10e
H
NMe2
38
H
H
H
10a
(0.2 mmol)
36
37
10a
(0.2 mmol)
37
(0.2 mmol)
(0.2 mmol)
100%!
100%!
75%!
50%!
25%!
0%!
36
10e
10a
75%!
50%!
25%!
0%!
•
•
•
10a
•
time (h)
1.2!
time (h)
1.2!
0!
0.3!
0.6!
0.9!
0!
0.3!
0.6!
0.9!
Figure 4. Relative rates of the reactions between LCuH and different amine transfer agents. Si* = Si(OEt)2Me. Conditions A: a 0.6
mL of a stock solution made from Cu(OAc)2 (3.6 mg), RꢀDTBMꢀSEGPHOS (26 mg), PPh3 (11.6 mg), HSi(OEt)2Me (0.32 mL, 2.0
mmol) and d8ꢀTHF (1.0 mL) is used. The progress of these experiments was monitored by 1H NMR.
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Conclusion
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In conclusion, we have designed a new type of amine transfer reagents that possess a 4ꢀ(dimethyamino)benzoate
group. The use of these reagents enabled the development of a general method to directly convert styrenes to chiral
secondary amines. This process was applicable to monoꢀ and disubstituted styrenes and allowed the use of a variety of
functionalized, structurally diverse amine transfer reagents, including those derived from carbohydrates, steroids, and
amino acid esters. The utility of this reaction was highlighted by its application to the synthesis of pharmaceutically
important drugs as well as the conjugation of other ones. Competition experiments have revealed that, relative to the
corresponding OꢀbenzoylꢀNꢀalkyl hydroxylamines, the modified amine transfer reagents (Oꢀ[4ꢀ
(dimethylamino)benzoyl]ꢀNꢀalkyl hydroxylamines) are less susceptible to direct reaction with LCuꢀH. The information
gained from this study should prove useful in the design and development of other CuHꢀcatalyzed processes.24
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Page 12 of 22
ASSOCIATED CONTENT
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Supporting Information.
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Experimental procedures and characterization data for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
8
9
AUTHOR INFORMATION
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Corresponding Author
sbuchwal@mit.edu
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors acknowledge the National Institutes of Health for financial support (GM58160). The content is solely the
responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
We thank Dr. M. T. Pirnot and Dr. Y. Wang for assistance in the preparation of this manuscript.
REFERENCES
(1) Nugent, T. C., Ed. Chiral Amine Synthesis: Methods, Developments and Applications; WileyꢀVCH: Weinheim,
Germany, 2010.
(2) Turner, N. J.; Carr, R. Biocatalytic Routes to Nonracemic Chiral Amines. In Biocatalysis in the Pharmaceutical
and Biotechnology Industries; Patel, R. N., Ed.; CRC Press LLC: Boca Raton, USA, 2006; pp. 743–755.
(3) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
(4) (a) Nugent, T. C.; ElꢀShazly, M. Adv. Synth. Catal. 2010, 352, 753. (b) Xie, J.; Zhu, S.; Zhou, Q. Chem. Rev.
2011, 111, 1713. Tufvesson, P.; LimaꢀRamos, J.; Jensen, J. S.; AlꢀHaque, N.; Neto, W.; Woodley, J. M. Biotech. Bioeng.
2011, 108, 1479. (c) Gopalaiah, K. Chem. Rev. 2013, 113, 3248. (d) Feng, X.; Du, H. Tetrahedron Lett. 2014, 55, 6959
(e) Bloch, R. Chem. Rev. 1998, 98, 1407. (f) Kobayashi, S.; Ishitani, H. Chem Rev. 1999, 99, 1069. (g) Friestad, G. K.;
Mathies, A. K. Tetrahedron 2007, 63, 2541. (h) Yamada, K.; Tomioka, K. Chem Rev. 2008, 108, 2874. (i) Kobayashi,
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S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (j) Yus, M.; GonzálezꢀGómez, J. C.; Foubelo, F.
Chem. Rev. 2011, 111, 7774. (k) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047.
(5) (a) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689. (b) Helmchen, G. IridiumꢀCatalyzed Asymmetric
Allylic Substitutions. In Iridium Complexes in Organic Synthesis; Oro, L. A.; Claver, C. Eds.; WileyꢀVCH, Weinheim,
Germany 2009; pp. 211–250; (c) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461; (d) Liu, W.ꢀB.; Xia, J.ꢀ
B.; You, S.ꢀL. Top. Organomet. Chem. 2012, 38, 155. (e) Tosatti, P.; Nelson, A.; Marsden, S. P. Org. Biomol. Chem.
2012, 10, 3147.
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2
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(6) (a) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc. Chem. Res. 2012, 45, 911. (b) Davies, H. M. L.; Manning, J. R.
Nature 2008, 451, 417. (c) Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.
(7) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (b) Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507. (c)
Hong, S.; Marks, T. J. Acc. Chem. Soc. 2004, 37, 673. (d) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. Int.
Ed. 2004, 43, 3368. (e) Hultzsch, K. C. Org. Biomol. Chem. 2005, 3, 1819. (f) Muller, T. E.; Hultzch, K. C.; Yus, M.;
Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (g) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367. (h) Huang,
L.; Arndt, M.; Gooβen, K.; Heydt, H.; Gooβen, L. J. Chem. Rev. 2015, 115, 2596.
(8) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9473. (b) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253. (c) Rainka, M. P.; Aye, Y.;
Buchwald, S. L. Proc. Natl Acad. Sci. U.S.A. 2004, 101, 5821.
(9) (a) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680. (b) Berman, A. M.; Johnson, J. S. J. Org.
Chem. 2006, 71, 219. (c) Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521. (d) Rucker, R. P.; Whittaker, A. M.;
Dang, H.; Lalic, G. Angew. Chem. Int. Ed. 2012, 51, 3953. (e) Yan, X.; Yang, X.; Xi, C. Catal. Sci. Technol. 2014, 4,
4169. (f) Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947. (g) Barker, T. J.; Jarvo, E. R. Synthesis 2011, 24, 3954.
(10) (a) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746. (b) Zhu, S.; Buchwald, S. L.
J. Am. Chem. Soc. 2014, 136, 15913. (c) Niljianskul, N.; Zhu, S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2015, 54,
1638. (d) Shi, S.; Buchwald, S. L. Nature. Chem. 2015, 7, 38.
(11) (a) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2013, 52, 10830. (b) Miki, Y.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2014, 16, 1498.
(12) In contrast to the large number of successful examples using dialkylamine transfer reagents (R2NOBz, R ≠ H) in
copperꢀmediated amination reactions, use of the analogous monoalkylamine transfer reagents [RN(H)OBz] remains
underdeveloped. For representative examples, see reference 9b, and (a) Yotphan, S.; Beukeaw, D.; Reutrakul, V.
Tetrahedron 2013, 69, 6627. (b) McDonald, S. L.; Wang, Q. Angew. Chem. Int. Ed. 2014, 53, 1867. (c) Matsuda, N.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2860.
(13) (a) Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 4666–4669. (b) PPh3 is used as an secondary ligand
due to the observed beneficial effects it has on CuꢀH catalyzed reactions. This concept was developed by Lipshutz:
Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem. Soc. 2003, 125, 8779.
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(14) Attempts to modify the properties of dialkylamine transfer reagents by adjusting the benzoate group have been
reported by Johnson.9c
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2
3
4
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7
8
9
(15) (a) Alkyl carboxylateꢀbased amine transfer reagents 13 and 14 were also tested. Reagent 14 containing a bulky
adamantyl group provided similar yields of 11b and 11c as 4ꢀ(dimethylamino)benzoate 10e. Due to the availability of
the 4ꢀ(dimethylamino)benzoic acid and its ease of removal after reaction,15b 4ꢀ(dimethylamino)benzoates were used
for most of this work. (b) 4ꢀ(Dimethylamino)benzoic acid is sparingly soluble in Et2O, EtOAc, or CH2Cl2, but readily
soluble in 2 M aqueous K2CO3.
10
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12
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(16) Attempts to use 10e in the hydroamination of β,βꢀdisubstituted styrenes or terminal unactivated alkenes gave
low yields of secondary amine products.
(17) (a) Grigg, R. D.; Van Hoveln, R.; Schomaker, J. M. J. Am. Chem. Soc. 2012, 134, 16131. (b) Van Hoveln, R. J.;
Schmid, S. C.; Schomaker, J. M. Org. Biomol. Chem. 2014, 12, 7655.
(18) Smithen, D. A.; Mathews, C. J.; Tomkinson, N. C. O. Org. Biomol. Chem. 2012, 10, 3756.
(19) Several methodologies have been developed to convert αꢀamino acid esters into the corresponding primary Nꢀ
hydroxylamines. For references, see: (a) Tokuyama, H.; Kuboyama, T.; Fukuyama, T. Org. Syn. 2003, 80, 207. (b)
Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 1981. (c) Bode, J. W.; Fukuzumi, T. J. Am.
Chem. Soc. 2009, 131, 3864.
(20) Sun, H.; Martin, C.; Kesselring, D.; Keller, R.; Moeller, K. D. J. Am. Chem. Soc. 2006, 128, 13761.
(21) Molander, G. A.; Brown, A. R. J. Org. Chem. 2006, 71, 9681.
(22) Formation of BnNH2 and the silylated ester 37 could be detected by GC/MS and 1H NMR analysis.
(23) The reduction of the dialkylamine transfer agent 36 is much slower. Approximately 60% of 36 was consumed
after 20 h under described conditions.
(24) A manuscript detailing the use of related modified amine transfer reagents to effect hydroamination of
unactivated internal alkenes is in press.
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Journal of the American Chemical Society
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ACS Paragon Plus Environment

O
CCl3
Journal of the American Chemical SociePtyage 16 of 22
O
OH
HN
Cl3C
N
Me
S
Me
Me
N
Me
Me
Me
Me
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CF3
O
NH
S
N
H
Me
F
N
Dysidenin
Ephedrine
BVT-116429
N
H
N
CO2H
Me
N
Me
O
CF3
ACS Paragon Plus Environment
F
Sensipar
PF-05105679

a) Traditional hydroamination
Page 17 of 2J2ournal of the American Chemical Society
R
R
R
Hydroamination
R
N
+
H NR2
1
2
3
4
5
R
R
1
2
3
b) CuH catalyzed hydroamination: synthesis of chiral tertiary amines
6
7
8
R
N
R
R
R
N
LCu-H
9
R
BzO
R
R
+
R
10
11
12
13
LCu-H
14
15
16
17
18
19
20
• mild conditions
• broad scope
1
4
3
electrophile
tertiary amine
CuL
5
R
R
6
nucleophile
21
c) This work: synthesis of chiral secondary amines
22
23
24
O
H
N
H
R
R
LCu-H
N
25
R
O
R
+
R
R
26
27
28
29
30
31
32
33
34
35
R'
7
1
8
electrophile
secondary amine
ACS Paragon Plus Environment
R' = H :
generally poor yields
R' = NMe2:
broad substrate scope, good yields

a
Journal of the American Chemical Society
a) Hydroamination of styrenes 9a-c using BnNHOBz (10a)
Page 18 of 22
Cu(OAc)2 (2.0 mol%)
Bn
R2
O
NH R2
H
N
1
2
(R)-L (2.2 mol%), PPh3 (4.4 mol%)
R1
R1
O
+
Bn
O
3
4
5
6
7
8
9
O
O
HSi(OEt)2Me (2.0 equiv)
THF (0.5 M), 40 °C, 16 h
PAr2
PAr2
9a-c
Bn
10a (1.2 equiv)
11a–c
O
Bn
Bn
NH
NH Me
NH
L = DTBM-SEGPHOS
Me
10
11
12
13
14
15
16
Me
Me
Ar = 3,5-(tBu)2-4-MeO-C6H2
11a
60% yield, 96% ee
11b
25% yield
11c
< 10% yield
b) Mechanistic rationale
c) Hydroaminationa of 9b and 9c using modified amine transfer reagents 10a–e
17
18
19
20
21
22
23
24
CuL R2
R1
9a-c
yield of 11b
90%
12a–c
Productive pathway
yield of 11c
O
H
N
BnNHOBz
60%
Non-productive pathway
Bn
O
10a
25
LCu-H
26
R
BnNHOBz
5
27
30%
10a
28
29
30
31
32
33
34
35
10a–e
OEt
11a–c
Me Si OBz
OEt
H
EtO Si OEt
Me
4-CF3
(10b)
4-NMe2
(10e)
R =
H
(10a)
2-MeO 4-MeO
LCu–OBz
(10c)
(10d)
d) Scope of different styrenes in hydroamination reactions using 10e (1.2 equiv)b
36
37
Bn
Bn
Bn
Bn
Bn
Bn
38
39
40
41
42
43
44
NH
NH
NH
NH
NH
NH
Me
BnO
Me
Me
EtO2C
Me
Me
OMe
11fc
yield ee
11a, 93% yield, 97% ee 11b, 84% yield, 94% ee 11cc, 89% yield, 96% ee 11d, 73% yield, 95% ee 11e, 88% yield, 96% ee
1 mmol 85% 95%
5 mmol 87% 95%
45
46
47
Bn
Bn
Bn
Bn
Bn
Bn
NH
NH
NH
NH
NH
48
49
50
NH
N
O
Me
Me
Me
Me
Me
Me
Br
Me
51
52
53
54
N
N
F
CF3
yield ee
SO2Ph
ACS Paragon Plus Environment
11h, 74% yield, 99% ee 11i, 82% yield, 97% ee 11j, 83% yield, 98% ee 11k, 92% yield, 95% ee
11l ortho- 90% 92%
11mmeta- 89% 94%
11n para- 92% 96%
11g, 86% yield, 92% ee
55
56

b)
Paag) e 19 of 22
N(H)Bn
Journal of the American Chemical Society
N(H)Bn
N(H)Bn
O
Si*
O
Si*
O
NBn2
Si*
O
O
O
O
O
O
O
O
O
O
O
1
Conditions A
Conditions A
2
3
4
5
6
7
8
+
+
+
d8-THF, 40 °C
d8-THF, 40 °C
H
NMe2
10e
H
NMe2
38
H
H
H
10a
(0.2 mmol)
37
10a
(0.2 mmol)
36
37
(0.2 mmol)
(0.2 mmol)
9
100%
100%
10
11
12
13
14
15
16
17
18
19
20
21
22
10e
10a
36
75%
50%
25%
0%
75%
•
•
•
10a
•
50%
25%
ACS Paragon Plus Environment
time (h)
time (h)
0%
0
0.3
0.6
0.9
1.2
0
0.3
0.6
0.9
1.2

NMe2
leaving group
Journal of the American Chemical Society
(LG)
Page 20 of 22
a)
b)
S
S
N
CF3
Conditions A
Conditions B
1
CF3
H
N
O
N
Cl
2
3
O
O
3
3
Me2N
Me2N
4
5
6
7
8
22 Chlopromazine
19 (1.2 equiv)
23 (1.0 equiv)
18
Cu(OAc)2 (2 mol%)
(S)-L (2.2 mol%)
PPh3 (4.4 mol%)
Cu(OAc)2 (3 mol%)
(R)-L (3.3 mol%)
PPh3 (6.6 mol%)
CF3
OtBu
O
H
N
Me
S
N
iPr
OtBu
9
10
11
12
13
14
15
16
17
iPr
HN
N
O
H
DEMS (2 equiv)
THF, RT, 16 h
Me
DEMS (2 equiv)
THF, RT, 16 h
LG
3
Me2N
21 (Sensipar)
81% yield, 89% ee
20
25 (Chlopromazine-Valine Conjugate)
24
(1.2 equiv)
82% yield, > 20:1 dr
(1.0 equiv)
c)
18
19
Cl
20
21
22
23
24
25
26
27
28
29
Conditions B
N
N
Me
H
N
Me
Cu(OAc)2 (4 mol%)
(S)-L (4.4 mol%)
PPh3 (8.8 mol%)
N
CO2Et
N
N
CO2Et
27 (1.0 equiv)
26 (Loratadine)
HSi(OEt)2Me (2 equiv)
THF, RT, 16 h
N
LG
Me
Me
Conditions A
CO2Et
NH
O
BnO
30
BnO
BnO
31
32
33
30 (Loratadine-Estrone conjugate)
85% yield, > 20:1 dr
28 (Estrone derivative)
29 (1.0 equiv)
34
35
d)
36
HO2C
NH
MeO2C
37
38
39
40
41
42
43
44
45
1) NaH, MeI
Me
Me
N
O
Me
Cu(OAc)2 (2 mol%)
(R)-L (2.2 mol%)
PPh3 (4.4 mol%)
Me
O
2) Conditions B
O
CO2Me
N
Cl
O
Me
Me
32 (1.0 equiv)
31 (Tufnil)
Me
N
O
O
Me
H
O
O
O
O
O
O
HSi(OEt)2Me (2 equiv)
THF, RT, 16 h
Me
Me
O
Me
Me
Me
Me
46
Me
47
Conditions A
Me
Me
O
O
Me
35 (Tufnil-Glucose conjugate)
O
HN
ACS Paragon Plus Environment
LG
48
49
50
51
73% yield, 17:1 dr
33 (Glucose derivative)
34 (1.1 equiv)

O
Me2N
Cu(OAc)2 (2-4 mol%)
(R)-L (2.2-4.4 mol%)
PPh3 (4.4-8.8 mol%)
Page 21 of 22
Journal of the American Chemical Society
= LG
N
N
OH
Me2N
R
N
N
NH
R''
1
2
3
4
5
6
O
(CDI)
O
R
R'
+
N
H
R''
R'
+
HSiMe(OEt)2 (2.0 equiv)
THF (0.5 M)
O
CH2Cl2, 0 °C to RT
HO
R
N
H
16
17
40 °C, 5 h or RT, 16 h
(1.2-1.3 equiv)
15
7
8
9
10
11
12 Me
13
O
OMe
NH
Me
Me
Me
Ph
Me
NH
NH
Me
NH
NH
Ph
Me
Me
Me
Me
14
15
17a, 91% yield, 96% ee
2 mol% 'Cu'
17c, 92% yield, >20:1 dr
2 mol% 'Cu'
17e, 66% yield, >20:1 dr
4 mol% 'Cu'
17b, 91% yield, 93% ee
2 mol% 'Cu'
17d, 88% yield, >20:1 dr
2 mol% 'Cu' [with (S)-L]
16
17
18
BnO
O
OMe
NH
O
OBn
NH
O
OtBu
O
OtBu
MeO
O
19
20
21
22
23
24
25
BnO
iPr
NH
iPr
NH
NH
Me
Me
Me
Me
Me
Me
17ga, 64% yield, >20:1 dr
4 mol% 'Cu'
17i, 71% yield, >20:1 dr
3 mol% 'Cu' [with (S)-L]
26
27
28
29
30
31
32
33
34
35
36
37
38
17j, 92% yield, 95% ee
2 mol% 'Cu'
17f, 59% yield, , >20:1 dr
17h, 79% yield, >20:1 dr
3 mol% 'Cu'
4 mol% 'Cu'
O
MeO
Ph
Cu(OAc)2 (5 mol%)
Ph
NH
MeO
O
MeO
O
Ph
(R)-L (5.5 mol%)
LG
SiEt3
+
N
H
N
HSiMe(OEt)2 (4 equiv)
LiOMe (5 equiv)
ACS Paragon Plus Environment
Cl
17k, 79% yield, 99% ee
2 mol% 'Cu'
THF (0.2 M), 45 °C, 40 h
17l, 55% yield, 97% ee

O
H
H
R
Journal of the American Chemical SocietyPage 22 of 22
LCu-H
N
N
R
O
R
+
Ar
R
Ar
Me2N
1
2
3
4
ACS Paragon Plus Environment
designed
chiral
arylalkene
amine electrophile
secondary amine
5