Protecting-group-free synthesis of amines: Synthesis of primary amines from aldehydes via reductive amination

Article abstract of DOI:10.1021/jo100004c

New methodology for the protecting-group-free synthesis of primary amines is presented. By optimizing the metal hydride/ammonia mediated reductive amination of aldehydes and hemiacetals, primary amines were selectively prepared with no or minimal formation of the usual secondary and tertiary amine byproduct. The methodology was performed on a range of functionalized aldehyde substrates, including in situ formed aldehydes from a Vasella reaction. These reductive amination conditions provide a valuable synthetic tool for the selective production of primary amines in fewer steps, in good yields, and without the use of protecting groups.

Full text of DOI:10.1021/jo100004c

pubs.acs.org/joc
Protecting-Group-Free Synthesis of Amines: Synthesis of Primary
Amines from Aldehydes via Reductive Amination
Emma M. Dangerfield,†,‡ Catherine H. Plunkett,†,‡ Anna L. Win-Mason,†,‡
Bridget L. Stocker,*,† and Mattie S. M. Timmer*,‡
‡
†Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand, and School of Chemical
and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
bstocker@malaghan.org.nz; mattie.timmer@vuw.ac.nz
Received January 4, 2010
New methodology for the protecting-group-free synthesis of primary amines is presented. By optimi-
zing the metal hydride/ammonia mediated reductive amination of aldehydes and hemiacetals,
primary amines were selectively prepared with no or minimal formation of the usual secondary
and tertiary amine byproduct. The methodology was performed on a range of functionalized
aldehyde substrates, including in situ formed aldehydes from a Vasella reaction. These reductive
amination conditions provide a valuable synthetic tool for the selective production of primary amines
in fewer steps, in good yields, and without the use of protecting groups.
Introduction
Traditionally, protecting groups have been used when pre-
paring primary amines via metal hydride reductive amina-
tion.7-9 Protecting groups have an important role in organic
synthesis,10 yet their incorporation into a synthetic route has
a number of disadvantages including an increase in the total
number of steps in the sequence (protection and deprotection
steps) and decreases in atom-economy.11 Protecting groups
also add functional groups and structural complexity to a
molecule, which can have detrimental effects on orthogon-
ality and reactivity. In metal hydride reductive aminations,
the use of protecting groups is crucial to prevent over-
alkylation (Scheme 1). In this reaction a carbonyl, typically
a ketone or an aldehyde (1), reacts with a protected amine (2,
R2 = alkyl, aryl) to form an imine (3) that is subsequently
Amines are an important class of compounds found in
many natural products, pharmaceuticals, and other valuable
organic molecules including dyes and agrochemicals.1,2
Although there are many synthetic transformations that can
be used to prepare amines,1 methodology for the selective
synthesis of primary amines is more limited. Of these, reduc-
tive aminations are particularly important,3-5 and reactions
utilizing molecular hydrogen as the reducing agent4 in the
presence of a suitable catalyst have proven very effective.5,6
The use of hydrogen gas under high pressure and tempera-
ture, however, shows significant functional group incompat-
ibility for double bonds and aromatic groups are also hydro-
genated. As an alternative, metal hydride reducing agents
can be employed, though the selective formation of primary
amines under these conditions is challenging.
(7) Kagan, F.; Rebenstorf, M. A.; Heinzelman, R. V. J. Am. Chem. Soc.
1957, 79, 3541–3544.
(8) Lauritsen, A.; Madsen, R. Org. Biomol. Chem. 2006, 4, 2898–2905.
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G.; Castellino, F. J. J. Org. Chem. 1993, 58, 4993–4996.
(1) Lawrence, S. A. Amines: Synthesis, Properties and Applications;
Cambridge University Press: Cambridge, 2004.
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7785–7811.
(3) Baxter, E.; Reitz, A. Organic Reactions; Wiley: New York, 2002;
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H.; Utsumi, T.; Ozawa, C.; Nakahara, Y.; Hojo, H.; Nakahara, Y. Tetra-
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A.; Takeuchi, S. Tetrahedron Lett. 2009, 50, 939–942. (c) Ali, A.; Van den
Berg, R. J. B. H. N.; Overkleeft, H. S.; Filippov, D. V.; Van der Marel, G. A.;
Codee, J. D. C. Tetrahedron Lett. 2009, 50, 2185–2188. (d) Timmer, M. S. M.;
Stocker, B. L.; Northcote, P. T.; Burkett, B. A. Tetrahedron Lett. 2009, 50,
7199–7204. (e) Fortin, M.; Kaplan, J.; Pham, K.; Kirk, S.; Andrade, R. B.
Org. Lett. 2009, 11, 3594–3597. (f) Khaliullin, F. A.; Klen, E. E. Russ. J. Org.
Chem. 2009, 45, 135–138.
(4) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002, 344,
1037–1057.
ꢀ
€
(5) Bodis, J.; Lefferts, L.; Muller, T. E.; Pestman, R.; Lercher, J. A. Catal.
Lett. 2005, 104, 23–28.
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Published on Web 07/28/2010
DOI: 10.1021/jo100004c
r
2010 American Chemical Society

Dangerfield et al.
JOCArticle
SCHEME 1. Reductive Amination of Aldehydes
SCHEME 2. Retrosynthesis of Primary Alkenylamines
alkenylamines (I) in one step from an alkyl halo-glycoside
precursor (II), itself readily available from the parent mono-
saccharide (III) in two steps18 (Scheme 2). Here, the typical
Vasella-reductive amination protocol16 involved the over-
night reflux of a suspension of Zn, NH4OAc (excess), NH3,
NaCNBH3, and the iodo-sugar in ethanol. Under these
conditions the primary alkylamine was produced exclusively
(>20:1 primary:secondary). Excess NH4OAc was crucial to
selectively obtaining the primary amine, and Dowex-Hþ ion
exchange chromatography proved most suitable for isolating
the product from the reaction mixture. With greater affinity
for the ion-exchange resin, the alkylamine was readily sepa-
rated from the ammonium salts by first washing the column
with water (to remove the salts), then eluting the amine
product with aqueous ammonia. Using these conditions 9
and 11 (entries 1 and 2, Table 1) were synthesized from 8 and
10 in excellent yields (95% and 91%) and chemoselectivities.
To gain insight into the factors responsible for the pre-
ferential formation of the primary amine, we investigated the
influence that pH has on the chemoselectivity of the reaction.
Using methyl iodo-glycoside 8 as a model substrate, the
Vasella-reductive amination was conducted over a pH range
from 7 to 12, and the resulting ratio of primary to secondary
amine products was recorded (Table 2). A neutral solution,
obtained by the addition of AcOH (10 equiv) to the reaction
mixture, gave the secondary amine as the major product
(4.5:5.5, 9:22, entry 1, Table 2). At pH 8, obtained when a
saturated solution of NH4OAc was used without the addi-
tion of AcOH or NH3, the formation of primary amine 9 was
favored (entry 2). Increasing the pH of the reaction mixture
to 10 using NH3 (10 equiv) improved the selectivity even
further with a 4:1 ratio of primary:secondary amine being
observed (entry 3). Having noted the beneficial influence that
increasing the pH has on chemoselectivity, 60 equiv of NH3
was then added. Under these conditions the primary amine
reduced (often with NaCNBH3)12 to give the desired amine
product 4. Without a protecting group (R2 = H), multiple
alkylation events typically occur, resulting in the formation
of the undesired secondary (6) ortertiary(7) amine products.3-5
This overalkylation is a consequence of the increased reac-
tivity of the primary amine product 4 (R2 = H) compared to
ammonia (2, R2 = H) in subsequent reductive amination
events.3,13,14 Though the formation of tertiary amines (7) can
be significantly reduced by using an excess of amine (2) or by
adjusting the pH,3 it is difficult to prevent the formation of
secondary amines (6). Generally, protected amines (2, R2 =
alkyl, aryl) are used as the amine source to avoid this problem.7-9
To provide alternative methodology for the synthesis of
primary amines, Miriyala et al. established a more selective
reductive amination protocol whereby primary amines were
produced from ketones using ammonia and titanium(IV)
isopropoxide-NaBH4.15 Unfortunately, the extension of this
methodology to aldehydes was ineffective and predominantly
resulted in secondary amine formation. This reduction in
selectivity is a consequence of the reduced steric bulk and
high reactivity of aldehydes when compared to ketones.13
Accordingly, the selective formation of primary amines from
aldehydes using reductive amination has continued to pose a
significant challenge.
Given the importance of primary amines as synthetic pro-
ducts and intermediates, we were interested in developing new
methodology for the preparation of amines from aldehydes
without the need for protecting groups. Recently, we reported a
procedure for the preparation of primary amines from methyl
glycosides using a Vasella-reductive amination reaction that did
not require the use of protecting groups.16 In this work, methyl
iodo-glycosides, derived from either D-ribose or D-xylose, were
efficiently converted into primary amines in a single synthetic
step using ammonia as the nitrogen source. For this methodo-
logy to have wider applicability, however, the scope and limi-
tations of this novel reductive amination protocol needed to be
determined. Herein, we report the results of our studies on the
chemoselective reductive amination of aldehydes.
1
was the only product observed by H NMR (>20:1, 9:22,
entry 4). From these results it appears that the pH-dependent
selectivity relates to the amount of free ammonia in solution.
At neutral or acidic pH, a greater proportion of ammonia will
beprotonated togive the non-nucleophilicammoniumcation.
As the pH increases, the availability of ammonia increases,
thereby favoring nucleophilic attack at the carbonyl and the
formationof the primary amineproduct. Interestingly, the use
of ammonia only leads to decomposition, and the addition of
NH4OAc is required to stablilize the amine product.
Using our optimized conditions, we then investigated the
applicability of the Vasella-reductive amination reaction
conditions for the synthesis of primary amines from other
methyl iodo-glycosides. Reaction of D-arabinoside 12 (entry
3, Table 1) proceeded uneventfully, giving the corresponding
Results and Discussion
In our protecting-group-free synthesis, a Vasella reaction17
and a reductive amination were used to prepare linear
(12) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971,
93, 2897–2904.
(13) Bowles, P.; Clayden, J.; Helliwell, M.; McCarthy, C.; Tomkinson,
M.; Westlund, N. J. Chem. Soc., Perkin Trans. 1 1997, 2607–2616.
(14) Pelter, A.; Rosser, R. M.; Mills, S. J. Chem. Soc., Perkin Trans. 1
1984, 717–720.
(15) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S. Tetrahedron 2004,
60, 1463–1471.
(16) Dangerfield, E. M.; Timmer, M. S. M.; Stocker, B. L. Org. Lett.
2009, 11, 535–538.
(17) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990–2016.
(18) Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M. R.;
Madsen, R. Synthesis 2002, 12, 1721–1727.
J. Org. Chem. Vol. 75, No. 16, 2010 5471

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TABLE 1. Vasella-Reductive Amination of Methyl Iodo-glycosides
aRatio obtained from 1H NMR of the crude material. bCombined yield of primary and secondary amines following purification. cSee Table 3.
TABLE 2. Vasella-Reductive Amination under Different pH Conditions
entry
additivea
pHb
ratioc (9:22)
1
2
3
4
AcOH (10 equiv)
none
aq NH3 (10 equiv)
aq NH3 (60 equiv)
7
8
10
12
4.5:5.5
3:2
4:1
>20:1
b
aConditions: Zn (5 equiv), NaCNBH3 (3 equiv), sat. ethanolic NH4OAc (20 mL/mmol). pH of the solution at the start of the reaction after all
reagents have been added. cRatio obtained from 1H NMR of the crude material.
alkenylamine 13 in an excellent yield (93%). As anticipated,
the stereochemistry around the furanose ring had no sig-
nificant effect on the yield or selectivity of the reaction.
Although byproducts from Vasella reactions have been well
documented, with reductive dehalogenation and the reduc-
tion of the aldehyde to the alcohol being the most common
degradation products,19 the Vasella-reductive amination
€
(19) Furstner, A.; Jumbam, D.; Teslic, J.; Weidmann, H. J. Org. Chem.
1991, 56, 2213–2217.
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TABLE 3. Vasella-Reductive Amination at Different Reaction Concentrations
entry
concentration
ratioa (21:23 amine)
yield (%)b
1
2
3
40 mL of sat. NH4OAc in ethanol per mmol
20 mL of sat. NH4OAc in ethanol per mmol
5 mL of sat. NH4OAc in ethanol per mmol
>20:1
9:1
1:1
50
93
99
aRatio obtained from 1H NMR of the crude material. bCombined yield of primary and secondary amines following purification.
occurred smoothly and with no other products observed. To
further investigate the applicability of our reaction, 2-deoxy-
riboside 14 was subjected to the same reductive amination
protocol (entry 4, Table 1). Again, exclusive formation of the
primary amine was observed with alkenylamine 15 being
isolated in good yield (81%). This result illustrated that the
absence of an R-hydroxyl function in the aldehyde substrate
did not adversely affect the efficiency or selectivity of the
reaction. Here, it should also be noted that alkenylamines
have a wide variety of applications, as in addition to their use
as intermediates in the synthesis of iminosugars,16,20 primary
alkenylamines have wide application as synthetic intermedi-
ates in total synthesis21 and in particular as substrates for
ring-closing metathesis.22
Given the promise of our methodology, we then explored
the role that the functional group pattern has on the chemo-
selectivity of the reaction. The fully protected methyl iodo-
glycosides of D-arabinose 1623 and D-ribose 1818 were sub-
jected to the Vasella-reductive amination conditions (entries
5 and 6). In both instances, the primary amines were the
major products, although the secondary amines were also
observed. Following Dowex-Hþ ion exchange chromato-
graphy, the relative integrals of the corresponding 1H NMR
signals were used to determine the ratio of primary to
secondary amine, and the assignments confirmed after se-
paration of the two amine products via silica gel chromatog-
raphy (DCM f DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1,
v/v/v/v). HRMS allowed for the identification of each
product, as did the HMBC correlations between the CH2-1
and the CH2-10 for the secondary amine product. Here, it is
interesting to note that the δ of C-1 of primary alkenylamines
17 (δ = 42.3 ppm) and 19 (δ = 42.5 ppm) was lower than the
corresponding δ of C-1 for the secondary amine product by
ca. 8 ppm. This observation was consistent for all primary
and secondary amines formed and provided a convenient
means by which to readily distinguish the two products. The
reduced selectivity observed for 16 and 18 suggested that
the functional group pattern of the substrate can affect the
chemoselectivity, though not as adversely as decreasing the
pH of the reaction solution.
Next, we turned our attention to the Vasella-reductive
amination of methyl 6-iodo-glucoside 20 (entry 7, Table 1) to
determine if the methodology was applicable to pyranosides.
When the reaction was conducted in more dilute conditions
(40 mL of sat. NH4OAc in ethanol with 16 mL of 30%
aqueous NH3 per mmol), only the desired primary amine 21
was produced (entry 1, Table 3); however, the yield was poor
because a significant amount of uncharacterizable degrada-
tion products was formed. Using the standard reaction
concentration (20 mL of NH4OAc in ethanol with 8 mL of
30% aqueous NH3 per mmol), the selectivity for primary
amine 21 was slightly reduced (21:23 = 9:1, entry 2), though
the overall yield was significantly improved (93%). To further
study the effect that concentration had on the reaction out-
come, more concentrated conditions (5 mL of sat. NH4OAc in
ethanol with 2 mL of 30% aqueous NH3 per mmol) were used
(entry 3). These conditions led to a reduction in chemoselec-
tivity, producing a 1:1 ratio of 21:23, though the overall yield
was improved with no observed degradation. From these
results, it is apparent that overdilution of the reaction mixture
leads to increased degradation and poor yields, presumably as
a consequence of a reduced rate in imine reduction, resulting
in imine degradation.
Following our investigations into the Vasella-reductive
amination methodology, we next explored the direct reduc-
tive amination of several aldehydes to determine whether the
Vasella step was a requirement for good selectivity. To
directly assess the effect of the initial Vasella reaction on
the chemoselectivity, the benzyl protected aldehyde 24 was
formed by subjecting methyl iodo-glycoside 18 to a Vasella
reaction, followed by standard workup procedures. Alde-
hyde 24 was then subjected to the reductive amination
conditions to give 19 in an equimolar ratio with the second-
ary amine (entry 1, Table 4). Though modest chemoselec-
tivity was obtained, this result nevertheless paralleled that
observed during the Vasella-reductive amination of riboside
18 (2:1, primary:secondary amine, entry 6, Table 1) and
suggested that the Vasella reaction had little effect on the
chemoselectivity of the reductive amination. Given this, we
sought to investigate the reductive amination of unfunctio-
nalized aldehydes. Here, nonanal (25) was subjected to the
reductive amination conditions with primary amine 26 being
formed exclusively and in excellent yield (98%) (entry 2,
(20) (a) Dangerfield, E. M.; Plunkett, C. H.; Stocker, B. L.; Timmer,
M. S. M. Molecules 2009, 14, 5298–5307. (b) Dangerfield, E. M.; Gulab,
S. A.; Plunkett, C. H.; Timmer, M. S. M.; Stocker, B. L. Carbohydr. Res.
2010, 345, 1360-1365.
(21) (a) Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Org. Lett.
2009, 11, 1179–1181. (b) Paderes, M. C.; Chemler, S. R. Org. Lett. 2009, 11,
1915–1918. (c) Zeng, W.; Chemler, S. R. J. Org. Chem. 2008, 73, 6045–6047.
(d) Fukumoto, H.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew.
Chem., Int. Ed. 2006, 45, 2731–2734.
(22) (a) Pavlyuk, O.; Teller, H.; McMills, M. C. Tetrahedron Lett. 2009,
50, 2716–2718. (b) Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.;
Ouyang, X.; Clark, W. M. Tetrahedron 2009, 65, 6291–6303. (c) Verhelst,
S. H. L.; Martinez, B. P.; Timmer, M. S. M.; Lodder, G.; Van der Marel,
G. A.; Overkleeft, H. S.; Van Boom, J. H. J. Org. Chem. 2003, 68, 9598–9603.
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2002, 43, 7577–7579.
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TABLE 4. Reductive Amination of Masked Aldehyde (Hemiacetal) and Aldehyde Substrates
aRatio obtained from 1H NMR of the crude material. bCombined yield of primary and secondary amines following purification.
Table 4). This result was significant because it illustrated that
hydroxyl substituents were not required for the selective
reductive amination of aldehydes and therefore markedly
increased the scope of the reductive amination methodology.
These results also indicated that the addition of zinc (for the
one-pot Vasella-reductive amination reaction) did not signifi-
cantly alter the outcome of the reaction and negates the
possibility of boron ester24 or zinc chelate25 formation having
a decisive influence on the chemoselectivity of the reaction.
Unfortunately, the unprotected aldehyde products from
the Vasella reaction of furanosides 8, 10, and 12 readily
condensed into polymeric mixtures of acetals and could not
be isolated for study in a reductive amination reaction that
was independent of the Vasella reaction.
Next, we examinedthe furanose series of hemiacetals27, 29,
and 31 (entries 3-5, Table 4). Reductive amination of D-
xylose (27) and 2-deoxy-D-ribose (29) gave the corresponding
primary amines, 28 and 30, in excellent selectivity and in good
yield (>85%). These results parallel those for the furanose
Vasella-reductive amination series (cf. entries 1-4, Table 1)
and expand the scope of the reaction to hemiacetals. To
investigate the influence that the hydroxylation pattern has
on the chemoselectivity, the unsubstituted furanoside 31 was
then subjected to the reductive amination conditions (entry 5,
Table 4). Here, the ratio of primary to secondary amine was
also good (11:1), although the yield for the reaction was
reduced (60%). Amine 32and itsdimer were the only products
observed, suggesting that the reduced yield for this reaction
was due to the formation of non-amine byproducts, which could
not be extracted from the salts using a Dowex-Hþ column.
(24) (a) Garlaschelli, L.; Mellerio, G.; Vidari, G. Tetrahedron 1989, 45,
7379–7386. (b) Dubois, L.; Fiaud, J.-C.; Kagan, H. B. Tetrahedron 1995, 51,
3803–3812.
(25) (a) Nieuwpoort, G.; Brussee, J.; Reedijk, J. Inorg. Chim. Acta 1983,
68, 131–135. (b) Rustagi, S. C.; Rao, G. N. J. Inorg. Nucl. Chem. 1974, 36,
1161–1163.
5474 J. Org. Chem. Vol. 75, No. 16, 2010

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Given our encouraging results, the reductive amination of
a series of pyranoses was then explored. First, D-glucose (33)
was treated with a saturated solution of NH4OAc in ethanol,
aqueous NH3, and NaCNBH3 to give 1-amino-1-deoxy-D-
glucitol (34) in good yield (87%) and with excellent selec-
tivity (>20:1, primary:secondary amine) (entry 6, Table 4).
Hemiacetals with decreasing hydroxylation were then sub-
jected to the reductive amination reaction, with hydroxy-
methylpyranose 35 (entry 7) yielding the corresponding
amine 36 with good selectivity (8:1), albeit in moderate
overall yield (65%). The absence of the hydroxymethyl
group (37, entry 8) did not significantly alter the monomer
to dimer ratio (7:1), and primary amine 38 was produced in
good yield. The mono- and dialkylated products could be
easily separated by flash column chromatography on silica
gel and through a comparison of the CH2N chemical shifts of
the two products, the primary and secondary amines could
be easily identified by 13C NMR [e.g., C-5 of 5-amino-
pentanol 38 has an upfield chemical shift (δ = 39.4 ppm)
compared to the C-5 of the secondary amine (δ = 47.7
ppm)]. HMBC correlations and HRMS were also used to
confirm the identity of the amines. Taken as a whole, these
results demonstrate the applicability of our methodology to
the synthesis of a variety of primary amines from different
aldehyde precursors, and in almost all instances, good chemo-
selectivity was observed.
charring at ∼150 °C. Column chromatography was performed
on silica gel (40-63 μm). Dowex W50-X8 acidic resin was used
for ion exchange chromatography. NMR peak assignments are
based on 2D NMR experiments (COSY, HSQC, and HMBC).
General Procedure for the Synthesis of Alkenylamines. To a
solution of methyl iodo-glycoside (1 mmol) in a saturated solu-
tion of NH4OAc in EtOH (20 mL) were added activated Zn (327
mg, 5 mmol), NaCNBH3 (188 mg, 3 mmol), and 30% aqueous
NH3 (8 mL). The mixture was stirred at reflux for 18 h, cooled to
room temperature, and concentrated under reduced pressure.
The residue was redissolved in H2O, loaded onto a Dowex Hþ
ion-exchange resin, and washed several times with H2O to
remove excess salt. The amine product was then eluted with
15% to 30% aqueous NH3. Further purification was achieved
using gradient flash chromatography (DCM/EtOH/MeOH/
30% aqueous NH3, 25/2/2/1 to 5/2/2/1, v/v/v/v). The alkenyla-
mines were converted to the HCl salts for characterization.
(2S,3S)-1-Amino-pent-4-ene-2,3-diol Hydrochloride (9). By
subjecting xyloside 8 (60.1 mg, 0.22 mmol) to the general
procedure for the synthesis of alkenylamines, alkenylamine 9
was obtained as the HCl salt (32 mg, 0.21 mmol, 95%). Rf =
0.37 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v);
[R]20 = -40.0 (c = 0.07, EtOH); IR (film) 3405, 3212, 2888,
D
1555, 1434, 1016 cm-1. 1H NMR (300 MHz, D2O) δ 5.71 (ddd,
J
3,4 = 6.4, J4,5-cis = 10.5 Hz, J4,5-trans = 17.1 Hz, 1H, H-4), 5.34
(d, J4,5-trans = 17.1 Hz, 1H, H-5-trans), 5.28 (d, J4,5-cis = 10.5 Hz,
1H, H-5-cis), 4.10 (dd, J2,3 = 5.0 Hz, J3,4 = 6.4 Hz, 1H, H-3),
4.05 (s, 1H, NH), 3.81 (ddd, J1a,2 = 3.3 Hz, J2,3 = 5.0 Hz, J1b,2
9.7 Hz, 1H, H-2), 3.15 (dd, J1a,2 = 3.3 Hz, J1a,1b = 13.2 Hz, 1H,
H-1a), 2.98 (dd, J1b,2 = 9.7 Hz, J1a,1b = 13.2 Hz, 1H, H-1b); 13
=
C
Conclusion
NMR (75 MHz, D2O) δ 135.8 (C4), 117.9 (C5), 73.9 (C3), 72.0
(C2), 42.0 (C1); HRMS(ESI) m/z calcd for [C5H11O2N þ H]þ
118.0863, obsd 118.0871.
We have demonstrated that primary amines can be selec-
tively produced from aldehydes via metal hydride reductive
amination without the need for protecting groups. The most
important influences on the chemoselectivity are pH, the
number of amine equivalents, and reaction concentration,
with ideal conditions being a pH of approximately 12, a large
excess of ammonia, and an aldehyde concentration of 20 mL
of sat. NH4OAc in ethanol per mmol. Overall, the reductive
amination methodology is applicable to a wide range of
functionalized substrates, and the yields of the primary
amines are typically good. Without requiring protecting
groups, the methodology is fast and efficient (and thus
atom-economic) and provides a valuable synthetic tool for
the selective formation of primary amines. The application
of this methodology in the protecting-group-free syntheses
of further natural products is currently underway.
(2S,3R)-1-Amino-pent-4-ene-2,3-diol Hydrochloride (11). By
subjecting riboside 10 (51.2 mg, 0.19 mmol) to the general
procedure for the synthesis of alkenylamines, alkenylamine 11
was obtained as the HCl salt (26 mg, 0.17 mmol, 91%). Rf =
0.41 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v);
[R]18 = þ8.2 (c = 0.28, EtOH); IR (film) 3345, 2946, 2835,
D
1651, 1450, 1018 cm-1. 1H NMR (300 MHz, D2O) δ 5.88 (ddd,
J
3,4 = 6.6, J4,5-cis = 10.5, J4,5-trans = 17.1 Hz, 1H, H-4), 5.35 (d,
J4,5-trans = 17.1 Hz, 1H, H-5-trans), 5.31 (d, J4,5-cis = 10.5 Hz,
1H, H-5-cis), 4.12 (dd, J2,3 = 5.6, J3,4 = 6.6 Hz, 1H, H-3), 3.81
(ddd, J1a,2 = 3.0, J2,3 = 5.6, J1b,2 = 9.7 Hz, 1H, H-2), 3.23 (dd,
J
J
1a,2 = 3.0, J1a,1b = 13.2 Hz, 1H, H-1a), 2.95 (dd, J1b,2 = 9.7,
1a,1b = 13.2 Hz, 1H, H-1b); 13C NMR (75 MHz, D2O) δ 135.4
(C4), 118.3 (C5), 74.0 (C3), 69.8 (C2), 41.1 (C1); HRMS(ESI)
m/z calcd for [C5H11O2N þ H]þ 118.0863, obsd 118.0873.
(2R,3R)-1-Amino-pent-4-ene-2,3-diol Hydrochloride (13). By
subjecting arabinoside 12 (274 mg, 1 mmol) to the general
procedure for the synthesis of alkenylamines, alkenylamine 13
was obtained as the HCl salt (143 mg, 93 mmol, 93%). Rf = 0.61
Experimental Section
Unless otherwise stated all reactions were performed under
atmospheric air. Hemiacetals 31, 35, and 37 were synthesized
according to the procedure by Tamaru and co-workers.26
Methyl iodo-glycosides were synthesized according to the pro-
cedure by Madsen and co-workers.18 The Zn dust was activated
by the careful addition of conc H2SO4, followed by decantation
and washing with EtOH (3ꢀ) and hexanes (3ꢀ), and storage
under dry hexanes. All solvents were removed by evaporation
under reduced pressure. Reactions were monitored by TLC
analysis on silica gel coated plastic sheets (0.20 mm, Polygram
SIL G/UV254) with detection by spraying with 20% H2SO4 in
EtOH followed by charring at ∼150 °C, by dipping in I2 in silica,
or by spraying with a solution of ninhydrin in EtOH followed by
(DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v); [R]20
=
D
þ50.6 (c = 1.0, EtOH); IR (film) 3412, 3252, 3045, 1632, 1432,
1013 cm-1. 1H NMR (500 MHz, D2O) δ 5.74 (ddd, J3,4 = 5.3,
J
4,5-cis = 10.5, J4,5-trans = 17.3 Hz, 1H, H-4), 5.23 (d, J4,5-trans
17.3 Hz, 1H, H-5-trans), 5.17 (d, J4,5-cis = 10.5 Hz, 1H, H-5-cis),
3.99(t, J3,4 =J2,3 = 5.3 Hz, 1H, H-3), 3.70 (ddd, J1a,2 =2.8, J2,3
=
=
5.3, J1b,2 = 9.9 Hz, 1H, H-2), 3.03 (dd, J1a,2 = 9.9, J1a,1b = 13.1
Hz, 1H, H-1a), 2.87 (dd, J1a,2 = 2.8, J1a,1b = 13.1 Hz, 1H,
H-1b); 13C NMR (125 MHz, D2O) δ 135.4 (C4), 118.2 (C5), 73.7
(C3), 69.7 (C2), 41.5 (C1); HRMS(ESI) m/z calcd for
[C5H11O2N þ H]þ 118.0868, obsd 118.0869.
(S)-5-Amino-pent-1-en-3-ol Hydrochloride (15). By subjecting
deoxyriboside 14 (100 mg, 0.38 mmol) to the general procedure
for the synthesis of alkenylamines, alkenylamine 15 was obt-
ained as the HCl salt (42 mg, 0.31 mmol, 81%). Rf = 0.4 (DCM/
EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v); [R]17D = -3.2
(26) Kojima, K.; Kimura, M.; Satoshi, U.; Tamaru, Y. Tetrahedron 2006,
62, 7512–7520.
J. Org. Chem. Vol. 75, No. 16, 2010 5475

Dangerfield et al.
JOCArticle
(c = 0.1, EtOH); IR (film), 3359, 3047, 2955, 2927, 2854, 1635,
H-3), 3.47 (ddd, J1b,2 = 4.1, J2,3 = 5.3, J1a,2 = 5.6 Hz, 1H, H-2),
5.89-5.82 (m, 2H, H-1a and H-1b); 13C NMR (125 MHz,
CDCl3) δ 138.5, 138.3 (Cq Ph), 135.8 (C4), 128.4-127.6 (CH
Ph), 119.2 (C5), 82.8 (C2), 80.5 (C3), 72.8 (CH2 Bn on C2), 70.3
(CH2 Bn on C3), 42.3 (C1); HRMS(ESI) m/z calcd for
[C19H24NO2]þ 298.1807, obsd 298.1804. Dimer: Rf = 0.72
(DCM/EtOH/MeOH/30% aq NH3, 95/2/2/1, v/v/v/v); HRMS-
(ESI) m/z calcd for [C38H44NO4]þ 578.3270, obsd 578.3263.
(2S,3S,4R)-1-Amino-hex-5-ene-2,3,4-triol Hydrochloride (21).
By subjecting glucoside 20 (890 mg, 2.93 mmol) to the general
procedure for the synthesis of alkenylamines, alkenylamine 21
was obtained as the HCl salt (501 mg, 2.74 mmol, 93%). Rf =
0.20 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v);
1428, 1134, 1056 cm-1; 1H NMR (500 MHz, D2O) δ 5.35 (ddd,
J3,4 = 6.1, J4,5b =10.5, J4,5a = 17.3 Hz, 1H, H-4), 5.06 (dd, J5a,5b
= 1.3, J4,5a = 17.3 Hz, 1H, H-5a), 5.04 (dd, J5a,5b = 1.3, J4,5b
=
10.5 Hz, 1H, H-5b), 4.04 (ddd, J3,4 = 6.1, J2a,3 = 5.2, J2b,3 = 7.3
Hz, 1H, H-3), 2.96 (m, 2H, H-1), 1.38 (m, 2H, H-2); 13C NMR
(125 MHz, D2O) δ 138.8 (C4), 115.8 (C5), 70.1 (C3), 36.3 (C1),
32.9 (C2); HRMS(ESI) m/z calcd for [C5H12NO]þ 102.0919,
obsd 102.0921.
(2R,3R)-2,3-Bis-benzyloxy-pent-4-enylamine Hydrochloride
(17). To a solution of methyl arabinoside 16 (50.0 mg, 0.110
mmol) in a saturated solution of NH4OAc in EtOH (2.2 mL)
were added activated Zn (36 mg, 0.550 mmol), NaCNBH3
(21 mg, 0.330 mmol), and 30% aq NH3 (0.88 mL). The mixture
was stirred at reflux for 18 h, cooled to room temperature, and
concentrated under reduced pressure. The residue was redis-
solved in 10 mL of EtOAc and made basic using 1 M NaOH. The
layers were separated, and the aqueous layer extracted with
EtOAc. Organic extracts were combined and washed with brine,
dried (MgSO4), and concentrated under reduced pressure to
obtain alkenylamine 17 together with the secondary amine
product, in a 3:1 ratio (primary:secondary), as a colorless oil
(29 mg, 0.096 mmol, 81%). Amine 17 was purified using
gradient flash chromatography (DCM/EtOH/MeOH/30% aq
NH3, 475/2/2/1 to 95/2/2/1, v/v/v/v), then converted to the HCl
salt. Rf = 0.31 (DCM/EtOH/MeOH/30% aq NH3, 95/2/2/1,
v/v/v/v); [R]20D = þ6.0 (c = 0.3, CHCl3); IR (film) 3371, 3087,
3064, 3030, 2924, 2866, 2054, 1955, 1641, 1586, 1496, 1454, 1390,
1352, 1307, 1207, 1088, 996, 927, 734, 697 cm-1. 1H NMR (500
[R]17 = þ6.6 (c = 1.0, EtOH); IR (film) 3320, 3227, 3046,
D
2925, 1622, 1550, 1409, 1342, 1127, 1066, 1016, 935, 840, 737
=
cm-1. 1H NMR(500 MHz, D2O)δ5.71(ddd, J4,5 =6.9, J5,6-cis
10.6, J5,6-trans = 17.2 Hz, 1H, H-5), 5.21 (d, J5,6-trans = 17.2 Hz,
1H, H-6-trans), 5.14 (d, J5,6-cis = 10.6 Hz, 1H, H-6-cis), 4.05 (dd,
J3,4 = 6.7, J4,5 = 6.9 Hz, 1H, H-4), 3.80 (ddd, J2,3 = 2.9, J1a,2 =
4.8, J1b,2 = 7.6 Hz, 1H, H-2), 3.36 (dd, J2,3 = 2.9, J3,4 = 6.7 Hz,
1H, H-3), 2.98 (m, 2H, H-1a and H-1b); 13C NMR (125 MHz,
D2O) δ 135.8 (C5), 118.4 (C6), 74.2 (C3), 73.2 (C4), 67.0 (C2),
42.3 (C1); HRMS(ESI) m/z calcd for [C6H14NO3]þ 148.0974,
obsd 148.0977.
General Procedure for the Synthesis of Glycamines. To a
solution of hemiacetal (1 mmol) in a saturated solution of
NH4OAc in EtOH (20 mL) were added NaCNBH3 (188 mg, 3
mmol) and 30% aq NH3 (8 mL). The mixture was stirred at
reflux for 18 h, cooled to room temperature, and concentrated
under reduced pressure. The residue was redissolved in H2O,
loaded on to a Dowex Hþ ion-exchange resin, and washed several
times with H2O to remove excess salt. The amine product was
then eluted with 15% to 30% aq NH3. The eluent was concen-
trated under reduced pressure.
MHz, CDCl3) δ 7.38-7.27 (m, 10H, CH Ph), 5.84 (ddd, J3,4
7.5, J4,5-cis = 10.6, J4,5-trans = 17.1 Hz, 1H, H-4), 5.34 (d, J4,5-cis
=
=
10.6 Hz, 1H, H-5cis), 5.33 (d, J4,5-trans = 17.1 Hz, 1H, H-5trans),
4.81 (d, JHa,Hb = 11.5 Hz, 1H, CHaHb Bn), 4.65 (d, JHa,Hb
11.9 Hz, 1H, CHaHb Bn), 4.62 (d, JHa,Hb = 11.5 Hz, 1H, CHaHb
Bn), 4.41 (d, JHa,Hb = 11.5 Hz, 1H, CHaHb Bn), 3.96 (dd, J2,3
5.7, J3,4 = 7.5 Hz, 1H, H-3), 3.50 (ddd, J1a,2 = 3.8, J2,3 = 5.7,
1b,2 = 7.7 Hz, 1H, H-2), 2.87 (dd, J1a,2 = 3.8, J1a,1b = 13.2 Hz,
=
=
Nonylamine Hydrochloride (26). By subjecting aldehyde 25
(430 mg, 3.03 mmol) to the general procedure for the synthesis of
glycamines, nonylamine 26 was obtained as the acetate salt,
which was then converted into the HCl salt by the addition of
1 M HCl (534 mg, 2.97 mmol, 98%). All spectroscopic data was
in full agreement with that of a commercial sample (Aldrich).
1-Amino-1-deoxy-D-arabinitol (28). By subjection of arabi-
nose (27) (150 mg, 1 mmol) to the general procedure for the syn-
thesis of glycamines, glycamine 28 was obtained as the acetate
salt. Addition of HCl (1 M), followed by concentration, gave the
HCl salt of 28 (128 mg, 0.85 mmol, 85%). Rf = 0.01 (DCM/
EtOH/MeOH/NH3 (aq) 5/2/2/1 v/v/v/v); [R]16D = þ14.8 (c =
1.2, H2O); IR (film), 3372, 3364, 2967, 2943, 1634, 1070, 1032
J
1H, H-1a), 2.73 (dd, J1b,2 = 7.7, J1a,1b = 13.2 Hz, 1H, H-1b);
13C NMR (125 MHz, CDCl3) δ 138.6, 138.4 (Cq Ph), 135.0 (C4),
128.4-127.6 (CH Ph), 119.0 (C5), 82.8 (C2), 81.5 (C3), 73.6
(CH2 Bn on C2), 70.6 (CH2 Bn on C3), 42.5 (C1); HRMS(ESI)
m/z calcd for [C19H24NO2]þ 298.1807, obsd 298.1808.
(2S,3R)-2,3-Bis-benzyloxy-pent-4-enylamine Hydrochloride
(19). To a solution of methyl riboside 18 (305 mg, 0.671 mmol)
in a saturated solution of NH4OAc in EtOH (13 mL) were added
activated Zn (219 mg, 3.36 mmol), NaCNBH3 (125 mg, 2.011
mmol), and 30% aq NH3 (5.3 mL). The mixture was stirred at
reflux for 18 h, cooled to room temperature, and concentrated
under reduced pressure. The residue was redissolved in 20 mL of
EtOAc and made basic using 1 M NaOH. The layer were sepa-
rated, and the aqueous layer was extracted with ethyl acetate
(2 ꢀ 20 mL). The organic extracts were combined, washed with
brine, dried (MgSO4), and concentrated under reduced pressure
to obtain alkenylamine 19 together with the secondary amine
product in a 2:1 ratio (primary:secondary), as a colorless oil (218
mg, 0.655 mmol, 98%). Amine 19 was purified using gradient
flash chromatography (DCM/EtOH/MeOH/30% aq NH3, 475/
2/2/1 to 95/2/2/1, v/v/v/v), then converted to the HCl salt. Rf =
0.23 (DCM/EtOH/MeOH/30% aq NH3, 95/2/2/1, v/v/v/v);
cm-1. 1H NMR (500 MHz, D2O) δ 3.99 (ddd, J2,3 = 1.8, J1a,2
=
5.4, J1b,2 = 7.4 Hz, 1H, H-2), 3.68, (dd, J4,5a = 2.9, J5a.5b = 11.8
Hz, 1H, H-5a), 3.57 (ddd, J4,5a = 2.9, J4,5b = 5.9, J3,4 = 8.9 Hz,
1H, H-4), 3.51 (dd, J4,5b = 5.9, J5a,5b = 11.8 Hz, 1H, H-5b), 3.27
(dd, J2,3 = 1.8, J3,4 = 8.9 Hz, 1H, H-3), 3.01 (m, 2H, H-1); 13
C
NMR (125 MHz, D2O) δ 71.0 (C2), 70.3 (C3), 66.2 (C4), 62.6
(C5), 42.4 (C1); HRMS(ESI) m/z calcd for [C5H14NO4]þ
152.0923, obsd 152.0918.
1-Amino-1,2-dideoxy-D-ribitol (30). By subjecting 2-deoxyri-
bose (29) (134 mg, 1 mmol) to the general procedure for the
synthesis of glycamines, glycamine 30 was obtained as the acetate
salt. Addition of HCl (1 M), followed by concentration, gave the
HCl salt 25 (117 mg, 0.87 mmol, 87%). Rf = 0.02 (DCM/EtOH/
MeOH/NH3 (aq) 5/2/2/1 v/v/v/v); [R]16D = þ16.3 (c = 1.0, H2O);
IR (film), 3375, 3342, 3297, 2948, 2917, 1471, 1014 cm-1. 1HNMR
(500 MHz, D2O) δ 3.57 (m, 2H, H-3, and H-5a), 3.48 (m, 2H, H-4,
and H-5b), 3.04 (m, 2H, H-1), 1.83 (dddd, J = 2.9, J = 6.2, J =
8.8, J2a,2b = 14.5 Hz, 1H, H-2a), 1.64 (dddd, J = 6.6, J = 8.2, J =
9.8, J2a,2b = 14.5 Hz, 1H, H-2b); 13C NMR (125 MHz, D2O) δ
74.2 (C4), 69.5 (C3), 62.2 (C5), 37.1 (C1), 29.2 (C2); HRMS(ESI)
m/z calcd for [C5H14NO3]þ 136.0974, obsd 136.0972.
[R]21 = -40.4 (c = 1, CHCl3); IR (film) 3379, 3064, 3030,
D
2865, 1952, 1675, 1586, 1454, 1349, 1206, 1089, 1066, 994, 927,
1
734, 696 cm-1. H NMR (500 MHz, CDCl3) δ 7.36-7.27 (m,
10H, CH Ph), 5.89 (ddd, J3,4 = 7.7, J4,5-cis = 10.5, J4,5-trans =
17.2 Hz, 1H, H-4), 5.37 (d, J4,5-cis = 10.5 Hz, 1H, H-5-cis), 5.34
(d, J4,5-trans = 17.2 Hz, 1H, H-5-trans), 4.70 (d, JHa,Hb = 11.4
Hz, 1H, CHaHb Bn), 4.65 (d, JHa,Hb = 11.9 Hz, 1H, CHaHb Bn),
4.56 (d, JHa,Hb = 11.4 Hz, 1H, CHaHb Bn), 4.38 (d, JHa,Hb =
11.9 Hz, 1H, CHaHb Bn), 3.89 (dd, J2,3 = 5.3, J3,4 = 7.7 Hz, 1H,
5476 J. Org. Chem. Vol. 75, No. 16, 2010

Dangerfield et al.
JOCArticle
4-Amino-butan-1-ol Hydrochloride (32). By subjecting furanol
31 (470 mg, 5.34 mmol) to the general procedure for the
synthesis of glycamines, glycamine 32 was obtained as the
acetate salt together with its secondary amine product in a
11:1 ratio (primary:secondary). Addition of HCl (1 M), fol-
lowed by concentration, gave a mixture of the corresponding
HCl salts (401 mg, 3.21 mmol, 60%). Primary and secondary
amines were separated using gradient flash chromatography
(DCM/EtOH/MeOH/30% aq NH3, 95/2/2/1 to 10/2/2/1, v/v/v/
v) and converted to the HCl salt for characterization. 27: Rf =
0.24 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v); IR
(film) 3374, 3280, 3042, 2982, 2844, 1634, 1443, 1405, 1054,
1033, 1015, 907, 698 cm-1. 1H NMR (500 MHz, D2O) δ 3.58 (t,
(C6), 31.5 (C3), 26.6 (C5), 21.7 (C4); HRMS(ESI) m/z calcd for
[C6H16NO2]þ 134.1176, obsd 134.1175. 6-(5,6-Dihydroxy-
hexylamino)-hexane-1,2-diol hydrochloride: Rf = 0.34 (DCM/
1
EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v); H NMR (500
MHz, D2O) δ 3.68 (ddd, J1a,2 = 3.9, J1b,2 = 6.8, J2,3 = 10.9 Hz,
2H, H-2), 3.56 (dd, J1a,2 = 3.9, J1a,1b = 11.7 Hz, 2H, H-1a), 3.45
(dd, J1b,2 = 6.8, J1a,1b = 11.7 Hz, 2H, H-1b), 3.02 (t, J5,6 = 7.9
Hz, 4H, H-6), 1.67 (m, 4H, H-5), 1.50 (m, 4H, H-3), 1.41 (m, 4H,
H4); 13C NMR (125 MHz, D2O) δ 71.3 (C2), 65.2 (C1), 47.3
(C6), 31.5 (C3), 25.4 (C5), 21.8 (C4); HRMS(ESI) m/z calcd for
[C12H28NO4]þ 250.2018, obsd 250.2020.
5-Amino-pentan-1-ol Hydrochloride (38). By subjecting pyr-
anose 37 (400 mg, 3.92 mmol) to the general procedure for the
synthesis of glycamines, glycamine 38 was obtained as the
acetate salt together with the secondary amine products in a
7:1 ratio (primary:secondary) and then converted to the HCl salt
(515 mg, 3.18 mmol, 81%). Primary and secondary amine
products were then separated using gradient flash chromatog-
raphy (DCM/EtOH/MeOH/30% aq NH3, 95/2/2/1 to 10/2/2/1,
v/v/v/v) and converted to the HCl salts for characterization. 38:
Rf = 0.44 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/1, v/v/v/v);
IR (film) 3425, 3294, 2935, 2868, 1623, 1517, 1472, 1208, 1130,
1022, 951, 736, 699 cm-1. 1H NMR (500 MHz, D2O) δ 3.58 (t,
J1,2 = 6.5 Hz, 2H, H-1), 2.98 (t, J3,4 = 7.4 Hz, 2H, H-4), 1.67 (tt,
J3,4 = 7.4 J2,3 = 7.6 Hz, 2H, H-3), 1.57 (tt, J1,2 = 6.5, J2,3 = 7.6
Hz, 2H, H-2); 13C NMR (125 MHz, D2O) δ 60.9 (C1), 39.3 (C4),
28.2 (C2), 23.4 (C3); HRMS(ESI) m/z calcd for [C4H11ON þ
H]þ 90.0913, obsd 90.0911. Bis(5-hydroxy-butyl)-amine hydro-
chloride: Rf = 0.45 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/
1, v/v/v/v); HRMS(ESI) m/z calcd for [C8H19O2N þ H]þ
162.1494, obsd 162.1492.
1-Amino-1-deoxy-D-glucitol Hydrochloride (34). By subjecting
33 (180 mg, 1 mmol) to the general procedure for the synthesis of
glycamines, glycamine 34 was obtained as the acetate salt.
Addition of HCl (1 M), followed by concentration, gave the
HCl salt of 34 (156 mg, 0.86 mmol, 86%). Rf = 0.01 (DCM/
J
J
1,2 = 6.7 Hz, 2H, H-1), 2.95 (t, J5,4 = 7.6 Hz, 2H, H-5), 1.64 (tt,
3,4 = 7.6, J4,5 = 7.6 Hz, 2H, H-4), 1.55 (tt, J1,2 = 6.7, J2,3 = 7.5
Hz, 2H, H-2), 1.39 (tt, J2,3 = 7.5, J3,4 = 7.6 Hz, 2H, H-3); 13
C
EtOH/MeOH/NH3 (aq) 5/2/2/1 v/v/v/v); [R]16 = -6.1 (c =
NMR (125 MHz, D2O) δ 61.2 (C1), 39.4 (C5), 30.6 (C2), 26.7
(C4), 21.9 (C3); HRMS(ESI) m/z calcd for [C5H13ON þ H]þ
104.1075, obsd 104.1070. 5-(5-Hydroxy-pentylamino)-pentan-
1-ol hydrochloride: Rf = 0.63 (DCM/EtOH/MeOH/30% aq
NH3, 5/2/2/1, v/v/v/v); IR (film) 3309, 3117, 2934, 2862, 1496,
D
1.5, H2O); IR (film), 3431, 3388, 2975, 2947, 1633, 1090, 1054,
1014 cm-1; 1H NMR (500 MHz, D2O) δ 3.87 (ddd J1a,2 = 3.2,
J2,3 = 5.2, J1b,2 = 9.5 Hz, 1H, H-2), 3.65 (m, 2H, H-6a, H-3)
3.58 (m, 1H, H-5), 3.48 (m, 2H, H-6b and H-4), 3.06 (dd, J1a,2
3.2, J1a,1b = 13.1 Hz, 1H, H-1a), 2.91 (dd, J1b,2 = 9.5, J1a,1b
=
1
=
1369, 1207, 1079, 1022, 734, 697 cm-1. H NMR (500 MHz,
13.1 Hz, 1H, H-1b); 13C NMR (125 MHz, D2O) δ 70.7 (C5), 70.6
(C4), 70.5 (C3), 69.9 (C2), 62.5 (C6), 41.8 (C1); HRMS(ESI) m/z
calcd for [C6H16NO5]þ 182.1028, obsd 182.1028.
D2O) δ 3.58 (t, J1,2 = 6.5 Hz, 4H, H-1), 2.82 (t, J4,5 = 7.3 Hz,
4H, H-5), 1.59 (tt, J3,4 = 7.3, J4,5 = 7.3 Hz, 4H, H-4), 1.55 (tt,
J
1,2 = 6.5, J2,3 = 7.6 Hz, 4H, H-2), 1.36 (tt, J2,3 = 7.6, J3,4 = 7.3
6-Amino-hexane-1,2-diol Hydrochloride (36). By subjecting
pyranose 35 (100 mg, 0.763 mmol) to the general procedure
for the synthesis of glycamines, glycamine 36 was obtained
together with secondary amine product in a 8:1 ratio (primary:
secondary) as the acetate salts, which were then converted into
the HCl salt by the addition of 1 M HCl (83.7 mg, 0.495 mmol,
65%). 36: Rf = 0.18 (DCM/EtOH/MeOH/30% aq NH3, 5/2/2/
1, v/v/v/v); IR (film) 3353, 3204, 2928, 2856, 1710, 1662, 1393,
1267, 1125, 1073, 1046, 1013, 883, 740 cm-1.1H NMR (500
MHz, D2O) δ 3.68 (ddd, J1a,2 = 3.9, J1b,2 = 6.8, J2,3 = 10.9 Hz,
1H, H-2), 3.56 (dd, J1a,2 = 3.9, J1a,1b = 11.7 Hz, 1H, H-1a), 3.45
(dd, J1b,2 = 6.8, J1a,1b = 11.7 Hz, 1H, H-1b), 2.98 (t, J5,6 = 7.7
Hz, 2H, H-6), 1.67 (m, 2H, H-5), 1.50 (m, 2H, H-3), 1.41 (m, 2H,
H-4); 13C NMR (125 MHz, D2O) δ 71.3 (C2), 65.2 (C1), 39.3
Hz, 4H, H-3); 13C NMR (125 MHz, D2O) δ 61.3 (C1), 47.7 (C5),
30.7 (C2), 26.4 (C4), 22.5 (C3); HRMS(ESI) m/z calcd for
[C10H23O2N þ H]þ 190.1807, obsd 190.1801.
Acknowledgment. The authors would like to acknowledge
the financial contributions of the Wellington Medical Research
Foundation, the Tertiary Education Commission (Top Achiever
doctoral scholarship, E.M.D.), Victoria University of Wellington
(postgraduate scholarship, Curtis-Gordon research scholarship,
C.H.P.), and Lottery Health Research (B.L.S. and M.S.M.T.).
Supporting Information Available: Full experimental details
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 16, 2010 5477