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Org. Synth. 2015, 92, 156-170
DOI: 10.15227/orgsyn.092.0156
Synthesis of Phosphoryl Ynamides by Copper-Catalyzed Alkynylation of Phosphoramidates. Preparation of Diethyl benzyl(oct-1-yn-1-yl)phosphoramidate
Submitted by John M. Read, Yu-Pu Wang, and Rick L. Danheiser*1
Checked by Erik Daa Funder and Erick M. Carreira
1. Procedure
A. Diethyl benzylphosphoramidate(1). A 250-mL, two-necked, heart-shaped flask (Note 1) equipped with a 32 x 16 mm, Teflon-coated, oval magnetic stir bar, a Liebig condenser fitted with a nitrogen inlet adapter, and a glass stopper is charged sequentially via syringe with benzylamine (3.19 mL, 3.13 g, 29.3 mmol, 2.0 equiv) (Note 2), 50 mL of diethyl ether (Note 3), and diethyl phosphite (1.91 mL, 2.06 g, 14.6 mmol, 1.0 equiv). Iodoform (5.76 g, 14.6 mmol, 1.0 equiv) (Note 4) is added to the reaction mixture in three equal portions by temporarily removing the glass stopper. A vigorous bubbling starts after the first addition. Before the bubbling completely settles, the next portion of iodoform is added in order to maintain the momentum of the reaction. The portions are added approximately within 1 minute. The initiation of the reaction is indicated by an increase in temperature and spontaneous reflux of the solvent that begins a few seconds after the addition of iodoform (Note 5). During the course of the reaction the color of the heterogeneous reaction mixture changes from light yellow to white (see photos below).
v92p0156-1.jpg
After 2.5 h, TLC analysis indicates the complete disappearance of diethyl phosphite (Note 6). The reaction mixture is then poured into a 250-mL, round-bottomed flask. The original two-necked flask is rinsed with 50 mL of CH2Cl2, which is added to the round-bottmed flask, and the solution is concentrated by rotary evaporation (20 °C, 20 mmHg) to afford 10.7 g of a thick light yellow suspension. This material is diluted with 40 mL of chloroform (Note 7), and the homogeneous solution is transferred to a 125-mL separatory funnel and washed with water (2 x 30 mL), 0.5% aqueous acetic acid (2 x 30 mL), water (2 x 50 mL), and saturated NaCl solution (1 x 50 mL). The light peach-colored organic layer is dried over 4 g of MgSO4 and filtered through a 30-mL sintered glass Büchner funnel (medium porosity, 30 mm diameter). The MgSO4 is washed with chloroform (3 x 10 mL) and the combined filtrate is concentrated by rotary evaporation (20 °C, 20 mmHg) to afford 6.3 g of a light yellow oil.
This material is dissolved in a minimum amount of 5:1 EtOAc-CH2Cl2 (ca. 8 mL) and loaded onto a column (75 mm diameter) of 160 g of silica gel (Note 8) prepared as a slurry in 5:1 EtOAc-CH2Cl2. Elution with 5:1 EtOAc-CH2Cl2 (30 mL fractions collected in test tubes) affords the product in fractions 18-130. These fractions are combined and the solvent is removed by rotary evaporation (20 °C, 20 mmHg). Further concentration at 20 °C, 0.5 mmHg over 16 h provides 3.18 g (89%) of phosphoramidate 1 as a viscous light yellow oil (Notes 9 and 10).
B. 1-Bromooct-1-yne (2). A 250-mL, one-necked, round-bottomed flask (Note 1) equipped with a 32 x 16 mm, Teflon-coated, oval magnetic stir bar, rubber septum, and nitrogen inlet needle is charged with 1-octyne (2.90 mL, 2.17 g, 19.7 mmol, 1.0 equiv) (Note 11) and 65 mL of acetone (Note 12). N-Bromosuccinimide (NBS) (3.86 g, 21.7 mmol, 1.1 equiv) (Note 13) is then added in one portion by temporarily removing the septum. The reaction mixture is stirred for 2 min to allow all of the NBS to dissolve. Silver(I) nitrate (0.335 g, 1.97 mmol, 0.1 equiv) (Note 14) is added in one portion by temporarily removing the septum, the flask is wrapped with aluminum foil, and the colorless suspension is stirred at room temperature for 3 h at which point TLC analysis shows complete consumption of octyne (Note 15).
The resulting white suspension is transferred to a 250-mL separatory funnel and diluted with 65 mL of cooled deionized water (4 °C) and 70 mL of pentane. The organic phase is separated and washed with a saturated aqueous Na2S2O3 solution (3 x 25 mL) and brine (50 mL), dried over 5 g of MgSO4, and filtered through a 150-mL sintered glass Büchner funnel (fine porosity, 60 mm diameter). The MgSO4 is washed with pentane (3 x 30 mL) and the filtrate is concentrated by rotary evaporation (20 °C, 20 mmHg) to yield 3.41-3.58 g (92-96%) of 2 as a light yellow oil, which is used in the next step without further purification (Notes 16 and 17).
C. Diethyl benzyl(oct-1-yn-1-yl)phosphoramidate (3). A 100-mL, one-necked, round-bottomed flask (Note 1) equipped with a 20 x 9 mm, Teflon-coated, oval magnetic stir bar, rubber septum, and nitrogen inlet needle is charged with diethyl benzylphosphoramidate (1) (2.70 g, 11.1 mmol, 1.0 equiv), copper(II) sulfate pentahydrate (0.416 g, 1.67 mmol, 0.15 equiv) (Note 18), 1,10-phenanthroline (0.600 g, 3.33 mmol, 0.30 equiv), and potassium phosphate (4.71 g, 22.2 mmol, 2.0 equiv) (Note 19). The flask is evacuated to 0.5 mmHg and then backfilled with nitrogen (repeated two more times), and then 5 mL of toluene (Note 20) is added. A separate 50-mL, one-necked, round-bottomed flask is charged with 1-bromooct-1-yne (2) (2.73 g, 14.4 mmol, 1.3 equiv) and fitted with a rubber septum and nitrogen inlet needle. Toluene (20 mL) is added and the solution of bromoalkyne is rapidly transferred into the 100-mL flask via a metal cannula and nitrogen pressure. The 50-mL flask is rinsed with two 1.5-mL portions of toluene. The reaction mixture is placed under reduced pressure via the vacuum manifold until bubbling ensues and then backfilled with argon; this is performed four times. The rubber septum is replaced with an 11-cm Liebig condenser fitted with a rubber septum and nitrogen inlet needle. The system is evacuated and backfilled with nitrogen twice after which the heterogeneous brown reaction mixture (see photo) is heated in a 95 °C oil bath for 24 h (750 rpm stirring) (Note 21) at which point TLC analysis indicates complete consumption of phosphoramidate 1 (Note 22).
v92p0156-2.jpg
The reaction mixture is cooled to room temperature and filtered through 5 g of Celite in a 30-mL sintered glass Büchner funnel (medium porosity, 30 mm diameter). The Celite is washed with 150 mL of EtOAc and the filtrate is concentrated to afford ca. 9 to 10 g of an orange oil. This material is dissolved in a minimum amount of CH2Cl2 (ca. 15 mL) and loaded onto a column (75 mm diameter) of 200 g of silica gel prepared as a slurry in 10:5:85 EtOAc-Et3N-hexanes. Elution with 10:5:85 EtOAc-Et3N-hexanes (30 mL fractions) affords the product in fractions 26-80. These fractions are combined, and the solvent is removed by rotary evaporation (20 °C, 20 mmHg). Further concentration at 20 °C, 0.5 mmHg over 16 h provides 3.16-3.27 g (81-84%) of ynamide 3 as a viscous yellow oil (Note 22).
2. Notes
1. All reaction glassware was flame-dried under vacuum (0.5 mmHg), back-filled with argon while hot, and then maintained under the inert atmosphere during the course of the reaction. The checkers used an atmosphere of nitrogen in all reactions described. The submitters used a 250-mL round-bottomed flask for Step A with a rubber septum equipped with a thermocouple probe in place of the glass stopper employed by the checkers.
2. The submitters used benzylamine (99%), which was purchased from Acros Organics, and diethyl phosphite (technical grade, 94%) purchased from Aldrich Chemical Company. Both were used as received. If the benzylamine appeared yellow or showed any impurities by 1H NMR analysis, distillation from CaH2 was necessary to obtain optimal results. The checkers used benzylamine (>99%) purchased from TCI and distilled it from CaH2 under an atmosphere of nitrogen. Diethyl phosphite (98%) was purchased from Acros Organics and used as received.
3. The submitters used Et2O (ultra low water) that was purchased from J.T. Baker and purified by pressure filtration through activated alumina prior to use. The checkers used Et2O purchased from Sigma Aldrich containing BHT as a stabilizer. Before use the solvent was first distilled and then passed through an activated alumina column embedded in a solvent purification system provided by LC Technology Solutions. The solvent was finally further dried overnight under argon using 4 Å microwave activated molecular sieves purchased from Sigma Aldrich.
4. The submitters used iodoform (99%) that was purchased from Aldrich Chemical Company and used as received. The checkers purchased iodoform (99%) from Fluka, and it was used as received.
5.
CAUTION: The rapid addition of iodoform results in a vigorous exothermic reaction. Care needs to be taken in this step. The checkers chose to add the iodoform in portions, while ensuring the mixture starts to reflux in order to initiate the reaction.
6. TLC analysis was performed with silica gel plates (2 cm x 5 cm, glass backed, purchased from EMD Chemicals) with ethyl acetate as eluent and visualization with Seebach's stain (2.5 g of phosphomolybdic acid, 1 g of Ce(SO4)2, and 6 mL conc H2SO4 dissolved in 94 mL of H2O). Benzylamine: Rf = 0.08, diethyl benzylphosphoramidate (1): Rf = 0.20, diethyl phosphite: Rf = 0.33. Iodoform and diiodomethane do not stain. The checkers found that it was helpful to elute the TLC plate several times to obtain clear resolution of diethyl phosphite and diethyl phosphoramidate 1.
7. Chloroform (ACS grade) was purchased from Mallinckrodt Chemicals and used as received, but the solvent should be checked for acidity. A sample of chloroform (ca. 5 mL) is shaken with an equal volume of deionized water and the aqueous layer is tested with pH paper. If a pH of less than 5 is obtained, then the chloroform is washed with saturated aqueous NaHCO3, dried over MgSO4, and filtered before use.
8. The submitters used silica gel (40-63 µm) that was purchased from Sorbent Technologies and used as received. The checkers used high purity grade silica gel with a pore size of 60 Å and a 230-400 mesh particle size purchased from Fluka. The submitters collected 30-mL fractions and obtained the product in fractions 13-74.
9. A second run on similar scale provided the product in 88% yield.
10. Diethyl benzylphosphoramidate (1) has the following spectroscopic properties: 1H NMR pdf(400 MHz, CDCl3) δ: 1.31 (td, J = 7.1, 0.9 Hz, 6 H), 2.87 (br s, 1 H), 3.96-4.17 (m, 6 H),7.27 - 7.37 (m, 5 H);13C NMR pdf(100 MHz, CDCl3) δ: 16.4 (d, J = 7.1 Hz), 45.6, 62.6 (d, J = 5.3 Hz), 127.45, 127.53, 128.7, 139.8 (d, J = 6.5 Hz); 31P NMR pdf(162 MHz, CDCl3) δ: 8.39; HRMS (ESI) [M + H]+ calcd for C11H19NO3P: 244.1097. Found: 244.1097; IR (neat): 3218, 2981, 2931, 2905, 1454, 1226, 1024, 958, 697, 494 cm-1; Anal. Calcd for C11H18NO3P: C, 54.32; H, 7.46; N, 5.76. Found: C, 54.13; H, 7.65; N, 5.63.
11. The submitters used 1-octyne (98%) that was purchased from Alfa Aesar and used as received. The checkers used 1-octyne (97%) purchased from Aldrich and used as received.
12. The submitters used acetone (histological grade) that was purchased from Mallinckrodt Chemicals and used as received. The checkers used a new bottle of acetone purchased from Sigma Aldrich Chromasolv (>99.9%).
13. The submitters used N-bromosuccinimide (NBS) (99%) that was purchased from Alfa Aesar and used as received. If the material was dark yellow in color, NBS was recrystallized from water as recommended using the procedure described previously.2 The checkers used N-bromosuccinimide (99%) purchased from Acros Organics and used it as received.
14. The submitters used silver(I) nitrate (99.9+% metal basis) which was purchased from Alfa Aesar and used as received. The checkers used silver(I) nitrate (99%) purchased from Acros Organics and used as received.
15. TLC analysis was performed with silica gel plates (2 cm x 5 cm, glass backed, purchased from EMD Chemicals) with hexanes as the eluent and visualization with KMnO4. 1-Octyne: Rf = 0.47, 1-bromooct-1-yne: Rf = 0.58. The checkers observed: 1-bromooct-1-yne: Rf = 0.64
16. The bromoalkyne product has a very distinct smell and the checkers recommend that all manipulations (especially evaporations) of the material be performed in a well ventilated hood.
17. This material was found to be of high purity provided that pure 1-octyne and NBS were used as starting materials. 1-Bromooct-1-yne (2) has the following spectroscopic properties: 1H NMR pdf(400 MHz, CDCl3) δ: 0.89 (t, J = 6.9 Hz, 3 H),1.21 - 1.43 (m, 6 H), 1.51 (app quint, J = 7.1 Hz, 2 H), 2.20 (t, J = 7.1 Hz, 2 H); 13C NMR pdf(100 MHz, CDCl3) δ: 14.2, 19.8, 22.7, 28.4, 28.6, 31.4, 37.6, 80.6; IR (neat): 2960, 2934, 2860, 1468, 1459, 1379, 1327, 725 cm-1; Anal. Calcd for C8H13Br: C, 50.81; H, 6.93; Br, 42.26. Found: C, 50.62; H, 7.08; Br, 42.09.
18. The submitters used copper(II) sulfate pentahydrate which was purchased from Mallinckrodt Chemicals and ground to a fine powder with a mortar and pestle before use. The checkers used copper(II) sulfate pentahydrate purchased from Merck and ground to a fine light blue powder before use (see picture).
v92p0156-3.jpg
19. The submitters used 1,10-phenanthroline (≥99%) purchased from Aldrich Chemical Company and potassium phosphate (97%, anhydrous) purchased from Acros Organics. Both were used as received. The checkers used 1,10-phenanthroline (99%) purchased from Lancaster and newly purchased potassium phosphate (97%, anhydrous) from Acros Organics.
20. The checkers used toluene (ACS grade) purchased from J.T. Baker and purified by pressure filtration through activated alumina prior to use. The submitters used toluene purchased from Fisher. Before use the solvent was passed through an activated alumina column embedded in a solvent purification system provided by LC Technology Solutions.
21. Very rapid stirring is crucial to achieve complete reaction due to the heterogeneity of the reaction mixture. The checkers used 750 rpm.
22. TLC analysis was performed with silica gel plates (2 cm x 5 cm, glass backed, purchased from EMD Chemicals) with 4:1:1 EtOAc-CH2Cl2-hexanes as eluent and visualization with KMnO4. Diethyl benzylphosphoramidate (1): Rf = 0.29, 1-bromooct-1-yne (2): Rf = 0.79,ynamide 3: Rf = 0.64. The checkers observed the following values: Diethyl benzylphosphoramidate (1): Rf = 0.14, 1-bromooct-1-yne (2): Rf = 0.83, ynamide 3: Rf = 0.57
23. Diethyl benzyl(oct-1-yn-1-yl)phosphoramidate (3) has the following spectroscopic properties: 1H NMR pdf(400 MHz, CDCl3) δ: 0.87 (t, J = 6.9 Hz, 3 H), 1.13 - 1.33 (m, 12 H), 1.40 (quint, J = 6.9 Hz, 2 H), 2.16 (td, J = 6.8, 2.9 Hz, 2 H), 3.95 - 4.17 (m, 4 H), 4.39 (d, J = 8.8 Hz, 2 H), 7.27 - 7.38 (m, 3 H), 7.39 - 7.46 (m, 2 H); 13C NMR pdf(100 MHz, CDCl3) δ:14.2, 16.2 (d, J = 7.2 Hz), 18.5 (d, J = 1.4 Hz), 22.7, 28.5, 29.3 (d, J = 1.2 Hz), 31.5, 55.1 (d, J = 5.8 Hz), 63.6 (d, J = 5.6 Hz), 65.0 (d, J = 5.0 Hz), 76.0 (d, J = 5.0 Hz), 128.0, 128.4, 128.9, 137.4 (d, J = 1.8 Hz); 31P NMR pdf(162 MHz, CDCl3) δ: 4.64; IR (neat): 2986, 2964, 2929, 2858, 2253, 1497, 1455, 1265, 1024, 974, 700, 596, 545 cm-1; HRMS (ESI)[M + H]+calcd for C19H31NO3P: 352.2036. Found: 352.2037; Anal. Calcd for C19H30NO3P: C, 64.94; H, 8.60; N, 3.99. Found: C, 64.85; H, 8.53; N, 3.97.
Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Alkynes substituted with electron-donating nitrogen functional groups exhibit unique reactivity in a variety of polar and pericyclic reactions. In recent years, ynamides have emerged as an exceptionally valuable class of building blocks for organic synthesis.3 Ynamides are significantly more stable than simple ynamines, are more easily stored and handled, and are more resistant to hydrolysis and polymerization. While most ynamides studied to date are carbonyl and sulfonyl derivatives of ynamines, very recently N-phosphoryl ynamides have attracted attention as especially useful substrates for a variety of synthetic transformations.4,5 Research in our laboratory has focused on the application of N-phosphoryl ynamides in [2 + 2] cycloadditions with ketenes where we have observed their reaction to occur at a rate as much as an order of magnitude faster than that of the corresponding N-carbomethoxy ynamides.5 As a result of this exceptional reactivity, N-phosphoryl ynamides function as particularly useful alkyne partners in our vinylketene-based benzannulation strategy for the synthesis of highly substituted carboaromatic and heteroaromatic compounds.5
Scheme 1 outlines the general method for the synthesis of N-phosphoryl ynamides employed in this article. In 2003, concurrent research in our laboratory6 and that of Hsung7 led to the development of complementary methods for the synthesis of ynamides via copper-promoted coupling of haloalkynes with several classes of amide derivatives. The extension of this chemistry to the N-alkynylation of phosphoramidates (Scheme 1) was introduced by Hsung and coworkers in 20114a and provides a convenient and efficient method for the preparation of this class of ynamides.
v92p0156-4.gif
A variety of methods are available for the preparation of the phosphoramidate reaction partners required in this strategy. In addition to the direct reaction of the corresponding amines with phosphoryl halides, phosphoramidates can be synthesized via methods involving electrosynthesis,8 copper-catalyzed oxidative coupling,9 the Todd-Atherton reaction,10 the Staudinger phosphite reaction,11 and a recently reported method involving the reaction of aldehydes with phosphoryl nitrenoids.12
Herein we describe the synthesis of phosphoramidate 1 by reaction of benzylamine with an iodophosphate generated in situ via the modified Todd-Atherton procedure introduced by Mielniczak and Łopusinski.13 This approach avoids the use of toxic diethyl chlorophosphate which is employed in the more popular direct phosphorylation route,14 and is competitive in terms of cost since diethyl phosphite is very inexpensive.
The mechanism of the Todd-Atherton and related reactions has been the subject of several mechanistic studies.15,16 A general mechanism for the transformation described in this article is outlined in the following scheme. Overall, two equivalents of the amine are required for reaction, though in principle the amine can be recovered in cases where it is valuable.
v92p0156-5
	.gif
The alkynyl bromide 2 employed for the N-alkynylation of phosphoramidate 1 is conveniently prepared via silver-catalyzed bromination of octyne with NBS following the method originally reported by Hofmeister and coworkers.17 This convenient method typically provides bromoalkynes in high yield without the need to deprotonate the terminal alkyne with strong base. Several examples of the application of this method have previously been described in Organic Syntheses.6b,18 In the case of bromooctyne 2, the crude product of the bromination reaction is obtained in high purity and can be used in the subsequent alkynylation step without a need for further purification.
The synthesis of ynamide 3 described here follows the general procedure described by Hsung and coworkers.4a Despite the high reaction temperature and relatively high catalyst loading, this method provides a convenient and reliable procedure for the synthesis of N-phosphoryl ynamides provided that they do not incorporate heat-sensitive functional groups in their structure. As in the case of other metal-catalyzed coupling reactions, it is important to note that the use of anhydrous K3PO4 is crucial to obtain optimal yields.19
In summary, the reactions described in this article provide an efficient and economical synthetic route to 3, and also serve to illustrate an excellent general method for the preparation of N-phosphoryl ynamides, an important emerging class of synthetic building blocks.

References and Notes
  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139. Email: danheisr@mit.edu. We thank the National Science Foundation (CHE-1111567) for generous financial support.
  2. Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88.
  3. For recent reviews on the synthesis and transformations of ynamides, see: (a) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17−26. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064−5106. (c) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840−2859. (d) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560-578.
  4. (a) DeKorver, K. A.; Walton, M. C.; North, T. D.; Hsung, R. P. Org. Lett. 2011, 13, 4862-4865. (b) Wang, X.-N.; Winston-McPherson, G. N.; Walton, M. C.; Zhang, Y.; Hsung, R. P.; DeKorver, K. A. J. Org. Chem. 2013, 78, 6233-6244. (c) DeKorver, K. A.; Hsung, R. P.; Song, W.-Z.; Wang, X.-N.; Walton, M. C. Org. Lett. 2012, 14, 3214-3217. (d) DeKorver, K. A.; Wang, X.-N.; Walton, M. C.; Hsung, R. P. Org. Lett. 2012, 14, 1768-1771.
  5. Willumstad, T. P.; Haze, O.; Mak, X. Y.; Lam, T. Y.; Wang, Y.-P.; Danheiser, R. L. J. Org. Chem. 2013, 78, 11450-11469.
  6. (a) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011-4014. (b) Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88−101.
  7. (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368-2369. (b) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151-1154.
  8. Torii, S.; Sayo, N.; Tanaka, H. Tetrahedron Lett. 1979, 46, 4471-4474.
  9. Fraser, J.; Wilson, L. J.; Blundell, R. K.; Hayes, C. J. Chem. Commun. 2013, 49, 8919-8921.
  10. (a) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc. 1945, 660-663. (b) Atherton, F.R.; Todd, A.R. J. Chem. Soc. 1947, 674-678.
  11. (a) Letsinger, R. L.; Schott, M. E. J. Am. Chem. Soc. 1981, 103, 7394-7396. (b) Nielsen, J.; Caruthers, M. H. J. Am. Chem. Soc. 1988, 110, 6275-6276. (c) Wilkening, I.; del Signore, G.; Hackenberger, C. P. R. Chem. Commun. 2008, 2932-2934. (d) Serwa, R.; Majkut, P.; Horstmann, B.; Swiecicki, J.-M.; Gerrits, M.; Krause, E.; Hackenberger, C. P. R. Chem. Sci. 2010, 1, 596-602.
  12. Xiao, W.; Zhou, C.-Y.; Che, C.-M. Chem. Commun. 2012, 48, 5871-5873.
  13. Mielniczak, G.; Łopusinski, A. Synth. Commun. 2003, 33, 3851-3859.
  14. For the synthesis of 1 via reaction of benzylamine with ClPO(OEt)2, see (a) Hammerschmidt, F.; Hanbauer, M. J. Org. Chem. 2000, 65, 6121-6131. (b) Kumar, G. D. K.; Saenz, D.; Lokesh, G. L.; Natarajan, A. Tetrahedron Lett. 2006, 47, 6281-6284.
  15. Kong, A.; Engel, R. Bull. Chem. Soc. Jpn. 1985, 58, 3671-3672.
  16. Troev, K.; Kirilov, E. M. G.; Roundhill, D. M. Bull. Chem. Soc. Jpn. 1990, 63, 1284-1285.
  17. Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem. Int. Ed. 1984, 23, 727−729
  18. Leroy, J. Org. Synth. 1997, 74, 212-215.
  19. Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org. Chem. 2008, 73, 9447-9450.

Appendix
Chemical Abstracts Nomenclature (Registry Number)

Diethyl benzylphosphoramidate: Phosphoramidic acid, N-(phenylmethyl)-, diethyl ester; (1) (53640-96-3)

Benzylamine: Benzenemethanamine; (100-46-9)

Diethyl phosphite: Phosphonic acid, diethyl ester; (762-04-9)

Iodoform: Methane, triiodo-; (75-47-8)

1-Bromooct-1-yne: 1-Octyne, 1-bromo-; (2) (38761-0)

N-Bromosuccinimide: 2,5-Pyrrolidinedione, 1-bromo-; (128-08-5)

1-Octyne; (629-05-0)

Silver(I) nitrate: Nitric acid silver(1+) salt (1:1); (7761-88-8)

Diethyl Benzyl(oct-1-yn-1-yl)phosphoramidate: Phosphoramidic acid, N-1-octyn-1-yl-N-(phenylmethyl)-, diethyl ester; (3) (1332480-36-0)

Copper(II) sulfate pentahydrate: Sulfuric acid copper(2+) salt (1:1), hydrate (1:5); (7758-99-8)

Potassium phosphate: Phosphoric acid, potassium salt (1:3); (7778-53-2)

1,10-Phenanthroline (66-71-7)

John M. Read was born in Laredo, Texas, in 1994. He is currently an undergraduate at the Massachusetts Institute of Technology and expects to receive his B.S. degree in chemistry in 2016. John joined the laboratory of Professor Rick Danheiser in 2013, and his research has focused on the synthesis of highly substituted polycyclic compounds and requisite precursors.
Yu-Pu Wang was born in Taipei, Taiwan. He received a B.S. degree in Chemistry in 2009 from Rice University working in the laboratory of Professor James M. Tour. He is currently pursuing a Ph.D. degree at the Massachusetts Institute of Technology in the research group of Professor Rick L. Danheiser and his work involves the development of new methods for the synthesis of highly substituted indoles and their application to the synthesis of natural products and polycyclic systems with interesting electronic properties.
Rick L. Danheiser received his undergraduate education at Columbia where he carried out research in the laboratory of Professor Gilbert Stork. He received his Ph.D. at Harvard in 1978 working under the direction of E. J. Corey on the total synthesis of gibberellic acid. Dr. Danheiser is the A. C. Cope Professor of Chemistry at MIT where his research focuses on the design and invention of new annulation and cycloaddition reactions, and their application in the total synthesis of biologically active compounds.
Erik Daa Funder obtained his Ph.D. from Aarhus University, Denmark in 2013. During his Ph.D. studies he worked under the supervision of Prof. Kurt V. Gothelf dealing with the target synthesis of small molecules and the development of new reactions. The Ph.D. studies included a six-month stay in the group of Prof. Phil S. Baran at the Scripps Research Institute, La Jolla, CA, USA working on C-H activation. Currently, as a postdoctroral associate in the group of Prof. Erick M. Carreira, he is pursuing the synthesis of hydroxylated steroids, as well as the development and optimization of new reactions.