Palladium catalyzed C(sp3)–H acetoxylation of aliphatic primary amines to γ-amino alcohol derivatives

Kang Chena, Ding Wanga, Zhao-Wei Lia, Zheng Liua, Fei Pana, Yun-Fei Zhanga and Zhang-Jie Shi*ab
aBeijing National Laboratory of Molecule Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Mlecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. E-mail:
bState Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

Received 13th June 2017 , Accepted 17th July 2017

First published on 27th July 2017

It still remains a major challenge to apply free primary amino groups as the directing group for aliphatic C–H functionalization. In this article, we used the protonation strategy to control the binding ability of primary amines and realized free amino group directed inert aliphatic C–H acetoxylation in good chemo- and regio-selectivity. This methodology provided a straightforward approach from primary amines to γ-amino alcohols.

Aliphatic amines are a very important class of structural units that widely exist in natural and synthetic compounds.1 Owing to their ubiquity and importance, the transformations of these compounds have attracted extensive attention in organic chemistry.2 In recent years, C–H bond functionalization has been regarded as one of the most promising and straightforward approaches to diversify the existing molecules.3 During the past few decades, progress in the C–H bond functionalization of aliphatic amines was mainly concentrated in various transformations initiated by the amine α C–H cleavage through the oxidation or hydrogen transfer strategy.4,5 However, direct transformations of the remote aliphatic C–H bonds of amines have rarely been investigated.6 It was difficult to realize the selectivity on more inert remote C–H bonds of amines in the presence of their α C–H bonds. Additionally, the tolerance of the electron-rich amine moiety in C–H activation, especially under oxidation conditions, was of urgent concern.

To approach these goals, various strategies based on steric or electronic controls have been developed (Scheme 1A). An early example of the remote C–H bond functionalization of non-protected amino acids in Shilov's system was reported by Sames’ group.7 Recently, Sanford and White correspondingly reported different types of remote C–H oxidations via Pt or Fe catalysis, respectively.8 In these studies, the electronic deactivation of the α C–H bonds of amines by Brønsted/Lewis acid-coordination to the N atom was the key point to facilitate such oxidations. With a different strategy, Hartwig and coworkers achieved terminally selective C–H borylation of tertiary amines via Ir catalysis.9 The outcome of the regioselectivity was considerably owing to the combination of steric repulsion, Lewis acid–base interaction, and hydrogen bonding.

image file: c7qo00432j-s1.tif
Scheme 1 The design of free amino group directed aliphatic C–H functionalization.

Besides non-directing strategies for the remote aliphatic C–H transformations of amines, the directing strategy was also regarded as a promising approach to control the reactivity and selectivity in this field. Among recent results, electronwithdrawing auxiliary-masked amino groups were conventionally adopted as directing groups in the remote C–H functionalization of amine derivatives.10 Obviously, it took extra steps to install such auxiliaries and later-on remove them from the products, which decreased the atom- and step-economy of the whole synthetic route. In 2014, a breakthrough has been made by Gaunt's group (Scheme 1B). A class of highly sterically hindered secondary aliphatic amines was successfully applied in Pd-catalyzed C–H functionalization via four or five-membered palladacycles.11 Very recently, they further extended this steric tethering strategy in the modification of primary amino alcohols by converting them to highly hindered N,O-ketals as key reactants.12 In this article, the author clearly pointed out that, although the nitrogen motif of the less sterically hindered primary amine was an excellent coordinating group for the transition metal catalyst, the formation of a stable bis(amine)-metal complex would deactivate the metal catalysts in the C–H activation step, which restricted the application of primary amino groups in aliphatic C–H functionalization.

To overcome this challenge in the direct C–H functionalization of primary amines, we searched for a more straightforward method to suppress the formation of the bis(amine)-metal complex other than installing steric controlling motifs. We envisioned that the protonation of amines would limit the coordination ability of the amine N to Pd catalysts under acidic conditions. In our hypothesis, the equilibriums among the free primary amino group, the protonated amine and the complex of the amine with electrophilic metal species were essential to control the reactivity of the substrates and catalysts (Scheme 1C).13 The mono(amine)-metal complex might afford the opportunity for aliphatic C–H functionalization through metal-assisted C–H cleavage.11,12 Moreover, the protonation of amines would enhance their stability to electrophilic or oxidative reagents, thus keeping the amino group tolerated in the relatively harsh reaction conditions as well as decreasing the by-products.7,8 Thus the appropriate acidity of the reaction system was critical to promote the desired direct C–H functionalization.

Based on our design, we initiated the study of the directed C–H acetoxylation of primary amines (Table 1). To explore the site- and chemo-selectivity among different types of primary and secondary aliphatic C–H bonds, we chose 3-methyloctan-3-amine (1a) as the model substrate. As is known, primary amines are quite susceptible to oxidants. To our delight, we still observed the C–H acetoxylation product 2a in the presence of Pd(OAc)2 as the catalyst, PhI(OAc)2 as the oxidant, and Ac2O as the additive in AcOH at 120 °C (entry 1). Reactions in other solvents were far less efficient (see the ESI). The acetoxylation selectively took place at the terminal C–H bond at the γ position to the amino group, leaving the β-methyl C–H bond, the most remote terminal C–H bond and the γ-secondary C–H bond untouched. This result was distinct from previous reports,8,9,11 and indicated the generation of the free amino group coordinated five-membered palladacycle intermediate in the catalytic process. Later on, Ac2O was not found to be beneficial for this acetoxylation, so we decided to add it after the acetoxylation reaction (entry 2). The yield was significantly improved. The reaction time screening indicated that 6 h heating was the best and the amount of oxidant could be decreased to 1.5 equivalents (entries 3–8). Other Pd catalysts didn't promote the efficiency (see Table S1, entries 5 and 9–11). Notably, the concentration of reaction solvent was critical (entries 8–11). The highest yield was obtained in 3.0 mL of AcOH (entry 10). Surprisingly, we observed the N-acetyl protected product without the addition of Ac2O albeit in a slightly lower yield (entry 12). We tried to add Pd(OAc)2 and PhI(OAc)2 in two batches and finally we got the aliphatic C–H acetoxylation product in 67% NMR yield and 64% isolated yield (entry 14). A large scale experiment was also conducted, but the yield was low (see Table S1, entry 19). According to control experiments (see the ESI), the limited yield of the C–H acetoxylation product was mainly attributed to the decomposition of both the primary amines and desired products in this reaction system.

Table 1 The optimization of reaction conditionsa

image file: c7qo00432j-u4.tif

Entrya Time (h) PhI(OAc)2 (equiv.) AcOH (mL) Yield
a The reactions were carried out on a 0.1 mmol scale. The yields were determined by 1H NMR analysis, with 1,3-benzodioxole as the internal standard.b Ac2O was added together with the amine substrate.c AcOH was removed in vacuo before step 2, and acylation conditions were Ac2O (2.0 equiv.), NEt3 (0.1 ml), and DCM (3.0 mL) at rt for 3 h.d The reaction was analyzed without step 2.e Pd(OAc)2 and PhI(OAc)2 were added in two batches.f Isolated yield of the combined parallel reactions (3 × 0.1 mmol scale) was obtained.
1b 12 2.0 1.0 15%
2 12 2.0 1.0 38%
3 9 2.0 1.0 44%
4 6 2.0 1.0 45%
5 3 2.0 1.0 36%
6 6 1.5 1.0 46%
7 6 1.2 1.0 38%
8c 6 1.5 1.0 50%
9c 6 1.5 2.0 56%
10c 6 1.5 3.0 62%
11c 6 1.5 4.0 53%
12d 6 1.5 3.0 60%
13c,e 6 1.5 3.0 63%
14c,e 6 2.0 3.0 67% (64%)f

With the optimal conditions in hand, we extended the substrate scope (Table 2). Generally, aliphatic primary amines with various backbones reacted smoothly to give the corresponding products in moderate to good yields. Substrate 1b which contained two ethyl groups afforded both mono- and di-acetoxylation products in a ratio of nearly 1[thin space (1/6-em)]:[thin space (1/6-em)]1 (2b and 2b′). Compared to 1a, when the amino group attached to the more internal carbon atom, the yield slightly decreased (2c). Medium-sized cyclic primary amines were also workable and products were obtained in acceptable yields (2d–2f). The ring sizes ranging from 6 to 8 didn't significantly affect the efficiency. Finally, 3,3-dimethylbutan-2-amine (1g), which has an α C–H bond to the amino group, also gave the desired product, albeit in very low yield. However, this observation might offer another opportunity to extend this chemistry.

Table 2 Aliphatic C–H acetoxylation of primary amines with various backbonesa
a Reactions were carried out on a 0.1 mmol scale. Pd(OAc)2 and PhI(OAc)2 were added in two batches. Isolated yields of the combined parallel reactions (3 × 0.1 mmol) were reported.b 1H NMR yield, with 1,3-benzodioxole as the internal standard.
image file: c7qo00432j-u5.tif

To determine the selectivity between aromatic and aliphatic C–H bonds, we tested aryl-substituted amines (Table 3). At an early stage, we found that if aryl groups were equipped at the α, β or γ position of amines, the corresponding substrates seriously decomposed (see Fig. S1). Further investigation showed that when aryl substituents were installed at δ (4j) or more remote positions (4a–4i), the stability of the substrates significantly improved and the aliphatic C–H acetoxylation smoothly took place. Substrates with electron-neutral (4a, 4b and 4j) and electron-deficient arenes (4c–4e, 4g) performed better than the electron-rich analogs (4f), which might arise from the oxidation of substrates under the reaction conditions. A variety of functional groups on aryl rings, such as methoxyl (4f), trifluoromethyl (4d), halogen (4c and 4e) and ester (4g), were well-tolerated, providing the opportunity for further functionalization. Amines with extensive aryl π systems, such as biphenyl (4h) and naphthyl (4i), also gave comparable yields.

Table 3 Aliphatic C–H acetoxylation of aryl-substituted primary aminesa
a Reactions were carried out on a 0.1 mmol scale. Pd(OAc)2 and PhI(OAc)2 were added in two batches. Isolated yields of the combined parallel reactions (3 × 0.1 mmol) were reported.b Pd(OAc)2 (10 mol%) and PhI(OAc)2 (1.5 eq.) were added once.
image file: c7qo00432j-u6.tif

We further explored the substrates containing various functional groups to construct complicated amino alcohol derivatives (Table 4). The α-methyl homoserine derivative (6a) was obtained in an acceptable yield. The efficiency was not promoted with a β-amino acid ester (6b), probably owing to the chelating effect with adjacent functional groups to the Pd center. Therefore, we installed functional groups at the remote terminal site to minimize such an influence. To our satisfaction, ε-amino alcohol derivatives, such as its esters (6c and 6d) and ether (6e), were converted to the desired amino diol derivatives. The substrate containing F at the ε-position also successfully participated in such a C–H acetoxylation (6f). A terminal phthalimide amine was suitable and the acetoxylation product (6g) with two different protected nitrogen motifs was obtained in good yield. In comparison, the substrate bearing the saccharin moiety showed an inferior result (6h), which could not be explained at this stage.

Table 4 Aliphatic C–H acetoxylation of functionalized primary aminesa
a Reactions were carried out on a 0.1 mmol scale. Pd(OAc)2 and PhI(OAc)2 were added in two batches. Isolated yields of the combination of three parallel reactions (3 × 0.1 mmol) were reported.b Pd(OAc)2 (10 mol%) and PhI(OAc)2 (1.5 eq.) were added once.c [thin space (1/6-em)]1H NMR yield, with 1,3-benzodioxole as the internal standard.
image file: c7qo00432j-u7.tif

To explore the potential application of this method, we conducted the further transformation of the desired products. The N,O-diacetyl amino alcohol 2a underwent complete hydrolysis to form the corresponding free amino alcohol 7, which was further converted to oxazinone 8 by the treatment with triphosgene (Scheme 2A). Alternatively, partial hydrolysis of 2a under milder conditions afforded N-protected amino alcohol 9, which was easily transferred into N-protected β-amino acid 10 in an excellent yield (Scheme 2B).

image file: c7qo00432j-s2.tif
Scheme 2 Transformations of the γ-amino alcohol derivative.

A series of experiments were further carried out to probe the reaction mechanism. No desired product was generated from acetamide 11 under standard conditions (eqn (1)). This result again confirmed that the free amino group rather than the amide group played a vital role as the directing group. To interpret the in situ acylation of the amino group, we firstly heated the amine 1a in AcOH for 6 h in the absence of PhI(OAc)2. Only a trace amount of acetamide 11 was detected, which implied that other more effective acylation pathways might exist (eqn (2)). We further investigated the reactivity of γ-acetoxyl amine 12, which was an intermediate in the reaction. We were glad to find that the acylation of 12 proceeded smoothly to form compound 2a under acidic conditions (eqn (3)).

image file: c7qo00432j-u1.tif(1)
image file: c7qo00432j-u2.tif(2)
image file: c7qo00432j-u3.tif(3)

This result indicated that the newly formed C–OAc motif was crucial for the in situ acylation reaction. We hypothesized that an intramolecular acyl transfer process was reasonable. This in situ acylation process, worked as a special “switch” to slowly turn off the reactivity of the free amino group (but not fast enough to prevent the generation of the di-acetoxylation product, see 2b′). It was still helpful to alleviate the undesirable oxidation of products, and also to simplify the isolation of products.

According to our investigations, we proposed the following mechanism (Scheme 3). A primary amine could coordinate with a Pd(II) catalyst under acidic conditions, tuned by the movement of acid–base disassociation equilibrium. Sequentially, the cleavage of the C–H bond took place and the five-membered palladacycle B was generated. In the presence of PhI(OAc)2, the Pd(II) intermediate B was further oxidized to Pd(IV) species C, which underwent the reductive elimination to form the C–O bond. Later on, the in situ protection of the amino group took place to afford the desired product.

image file: c7qo00432j-s3.tif
Scheme 3 Possible mechanism of the free amino group directed aliphatic C–H acetoxylation.

When we were submitting this manuscript, some related studies on the C(sp3)–H arylation of aliphatic primary amines using a transient directing group were reported.14

In conclusion, we reported a straightforward functionalization of free aliphatic primary amines through Pd catalyzed C–H acetoxylation. The protonation of free amines is essential to adjust the coordination of less hindered primary amines to Pd catalyst to trigger the C–H palladation. The acetoxylation reaction selectively occurred on the aliphatic C–H bond at the γ position through a 5-membered palladacycle as a key intermediate. γ-Amino alcohol derivatives were successfully synthesized directly from primary amines. Further improvement of this methodology and the exploration of new chemistry based on this design are underway.

Conflicts of interest

The authors declare no competing financial interest.


The support of this work by the “973” Project from the MOST of China (2015CB856600, 2013CB228102) and NSFC (No. 21332001) is gratefully acknowledged.


  1. E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem., 2014, 57, 10257 CrossRef CAS PubMed.
  2. (a) S. A. Lawrence, Amines: Synthesis, Properties and Applications, Cambridge University Press, New York, 2004 Search PubMed; (b) T. C. Nugent, Chiral Amine Synthesis: Methods, Development and Applications, Wiley-VCH Verlag, Weinheim, 2010 Search PubMed; (c) T. E. Mueller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795 CrossRef CAS PubMed; (d) J.-H. Xie, S.-F. Zhu and Q.-L. Zhou, Chem. Rev., 2011, 111, 1713 CrossRef CAS PubMed.
  3. (a) K. Godula and D. Sames, Science, 2006, 312, 67 CrossRef CAS PubMed; (b) M. C. White, Science, 2012, 335, 807 CrossRef CAS PubMed; (c) T. Newhouse and P. S. Baran, Angew. Chem., Int. Ed., 2011, 50, 3362 CrossRef CAS PubMed; (d) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960 CrossRef CAS PubMed.
  4. For selected reviews on oxidative amine α C–H bond cleavage, see: (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335 CrossRef CAS PubMed; (b) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014, 53, 74 CrossRef CAS PubMed; (c) J. W. Beatty and C. R. J. Stephenson, Acc. Chem. Res., 2015, 48, 1474 CrossRef CAS PubMed.
  5. (a) X. Zhang, A. Fried, S. Knapp and A. S. Goldman, Chem. Commun., 2003, 2060 RSC; (b) A. D. Bolig and M. Brookhart, J. Am. Chem. Soc., 2007, 129, 14544 CrossRef CAS PubMed; (c) B. Sundararaju, M. Achard, G. V. M. Sharma and C. Bruneau, J. Am. Chem. Soc., 2011, 133, 10340 CrossRef CAS PubMed. For selected reviews, see: (d) B. Peng and N. Maulide, Chem. – Eur. J., 2013, 19, 13274 CrossRef CAS PubMed; (e) D. Seidel, Acc. Chem. Res., 2015, 48, 317 CrossRef CAS PubMed.
  6. Some recent references on Pd-catalyzed C(sp2)–H acetoxylation, see: (a) P. Y. Choy, C. P. Lau and F. Y. Kwong, J. Org. Chem., 2011, 76, 80 CrossRef CAS PubMed; (b) P. Y. Choy, F. Y. Kwong, Y. Q. Li, Q. L. Yang, P. Fang, T. S. Mei and D. Zhang, Org. Lett., 2013, 15, 270 CrossRef CAS PubMed; (c) Y. Q. Li, Q. L. Yang, P. Fang, T. S. Mei and D. Zhang, Org. Lett., 2017, 19, 2905 CrossRef CAS PubMed.
  7. B. D. Dangel, J. A. Johnson and D. Sames, J. Am. Chem. Soc., 2001, 123, 8149 CrossRef CAS PubMed.
  8. (a) M. Lee and M. S. Sanford, J. Am. Chem. Soc., 2015, 137, 12796 CrossRef CAS PubMed; (b) J. M. Howell, K. Feng, J. R. Clark, L. J. Trzepkowski and M. C. White, J. Am. Chem. Soc., 2015, 137, 14590 CrossRef CAS PubMed.
  9. Q. Li, C. W. Liskey and J. F. Hartwig, J. Am. Chem. Soc., 2014, 136, 8755 CrossRef CAS PubMed.
  10. For examples of masked amines as the directing groups for C(sp3)–H functionalization, see: (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. Soc., 2005, 127, 13154 CrossRef CAS PubMed; (b) G. He and G. Chen, Angew. Chem., Int. Ed., 2011, 50, 5192 CrossRef CAS PubMed; (c) N. Rodríguez, J. A. Romero-Revilla, M. Á. Fernández-Ibáñez and J. C. Carretero, Chem. Sci., 2013, 4, 175 RSC; (d) M. Fan and D. Ma, Angew. Chem., Int. Ed., 2013, 52, 12152 CrossRef CAS PubMed; (e) C. Wang, C. Chen, J. Zhang, J. Han, Q. Wang, K. Guo, P. Liu, M. Guan, Y. Yao and Y. Zhao, Angew. Chem., Int. Ed., 2014, 53, 9884 CrossRef CAS PubMed; (f) K. S. L. Chan, M. Wasa, L. Chu, B. N. Laforteza, M. Miura and J.-Q. Yu, Nat. Chem., 2014, 6, 146 CrossRef CAS PubMed; (g) H. Jiang, J. He, T. Liu and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 2055 CrossRef CAS PubMed. For recent reviews, see: (h) G. Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013, 52, 11726 CrossRef CAS PubMed; (i) O. Daugulis, J. Roane and L. D. Tran, Acc. Chem. Res., 2015, 48, 1053 CrossRef CAS PubMed; (j) Q. Li, S.-Y. Zhang, G. He, W. A. Nack and G. Chen, Adv. Synth. Catal., 2014, 356, 1544 CrossRef CAS; (k) L. V. Desai, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 9542 CrossRef CAS PubMed.
  11. (a) A. McNally, B. Haffemayer, B. S. L. Collins and M. J. Gaunt, Nature, 2014, 510, 129 CrossRef CAS PubMed; (b) A. P. Smalley and M. J. Gaunt, J. Am. Chem. Soc., 2015, 137, 10632 CrossRef CAS PubMed; (c) C. He and M. J. Gaunt, Angew. Chem., Int. Ed., 2015, 54, 15840 CrossRef CAS PubMed.
  12. J. Calleja, D. Pla, T. W. Gorman, V. Domingo, B. Haffemayer and M. J. Gaunt, Nat. Chem., 2015, 7, 1009 CrossRef CAS PubMed.
  13. (a) G. Cai, Y. Fu, Y. Li, X. Wan and Z. Shi, J. Am. Chem. Soc., 2007, 129, 7666 CrossRef CAS PubMed; (b) I. Omae, Chem. Rev., 1979, 79, 287 CrossRef CAS; (c) A. D. I. Ryabov, K. Sakodinskaya and A. K. Yatsimirsky, J. Chem. Soc., Dalton Trans., 1985, 2629 RSC.
  14. (a) Y. Xu, M. C. Young, C. Wang, D. M. Magness and G. Dong, Angew. Chem., Int. Ed., 2016, 55, 9084 CrossRef CAS PubMed; (b) Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 14554 CrossRef CAS PubMed; (c) Y. Liu and H. Ge, Nat. Chem., 2016, 9, 26 Search PubMed.


Electronic supplementary information (ESI) available: Experimental procedures and characterization data for all new compounds. See DOI: 10.1039/c7qo00432j
These authors equally contributed to this research

This journal is © the Partner Organisations 2017